Sulfonamido substituted imidazopyridines

ABSTRACT

Imidazopyridine compounds that contain sulfonamide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/322,262, filed Dec. 17, 2002, now Pat. No. 6,696,465, which is acontinuation of U.S. application Ser. No. 10/165,002, filed Jun. 7,2002, now Pat. No. 6,525,064, which is a continuation-in-part of U.S.application Ser. No. 10/016,073, filed Dec. 6, 2001, now abandoned,which claims the benefit of Provisional Application No. 60/254,228,filed Dec. 8, 2000.

FIELD OF THE INVENTION

This invention relates to imidazopyridine compounds that havesulfonamide functionality at the 1-position, and to pharmaceuticalcompositions containing such compounds. A further aspect of thisinvention relates to the use of these compounds as immunomodulators, forinducing cytokine biosynthesis in animals, and in the treatment ofdiseases, including viral and neoplastic diseases. The invention alsoprovides methods of making the compounds and intermediates used in theirsynthesis.

BACKGROUND OF THE INVENTION

The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system,Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c] quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537-1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substitutedderivatives thereof were later found to be useful as antiviral agents,bronchodilators and immunomodulators. These are described in, interalia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986;5,268,376; 5,346,905; and 5,389,640.

Substituted 1H-imidazopyridine-4-amine compounds useful as immuneresponse modifiers are described in U.S. Pat. Nos. 5,446,153; 5,494,916;and 5,644,063. The compounds described in these patents do not haveamine containing substitution at the 1-position. Certain1H-imidazo[4,5-c]quinolin-4-amines that have amide, sulfonamide, andurea functionality at the 1-position are described in PCT PublicationsWO 00/76505, WO 00/76518 and U.S. Pat. No. 6,331,539. The disclosures ofall the above-mentioned patents and published patent applications areincorporated herein by reference.

Despite these recent discoveries of compounds that are useful as immuneresponse modifiers, there is a continuing need for compounds that havethe ability to modulate the immune response, by induction of cytokinebiosynthesis or other mechanisms.

SUMMARY OF THE INVENTION

We have found a new class of compounds that are useful in inducingcytokine biosynthesis in animals. Accordingly, this invention providesimidazopyridine-4-amine compounds that have sulfonamide functionality atthe 1-position. The compounds which have been found to be usefulinducers of cytokine biosynthesis are defined by Formula (I), which isdescribed in more detail infra. Formula (I) is as follows:

wherein X, Y, Z, R₁, R₂, R₃, R_(4,) and R₅ are as defined herein.

The compounds of Formula (I) are useful as immune response modifiers dueto their ability to induce cytokine biosynthesis and otherwise modulatethe immune response when administered to animals. This makes thecompounds useful in the treatment of a variety of conditions such asviral diseases and tumors that are responsive to such changes in theimmune response.

The invention further provides pharmaceutical compositions containingthe immune response modifying compounds, and methods of inducingcytokine biosynthesis in an animal, treating a viral infection in ananimal, and/or treating a neoplastic disease in an animal byadministering a compound of Formula (I) to the animal.

In addition, the invention provides methods of synthesizing thecompounds of the invention and intermediates useful in the synthesis ofthese compounds.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned earlier, we have found that certain compounds inducecytokine biosynthesis and modify the immune response in animals. Suchcompounds are represented by Formula (I) below:

wherein

-   -   X is alkylene or alkenylene;    -   Y is —SO₂—;    -   Z is a bond or —NR₆—;    -   R₁ is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of        which may be unsubstituted or substituted by one or more        substituents independently selected from the group consisting        of:        -   -alkyl;        -   -alkenyl;        -   -aryl;        -   -heteroaryl;        -   -heterocyclyl;        -   -substituted cycloalkyl;        -   -substituted aryl;        -   -substituted heteroaryl;        -   substituted heterocyclyl;        -   —O-alkyl;        -   —O-(alkyl)₀₋₁-aryl;        -   —O-(alkyl)₀₋₁-substituted aryl;        -   —O-(alkyl)₀₋₁-heteroaryl;        -   —O-(alkyl)₀₋₁-substituted heteroaryl;        -   —O-(alkyl)₀₋₁-heterocyclyl;        -   —O-(alkyl)₀₋₁-substituted heterocyclyl;        -   —COOH;        -   —CO—O-alkyl;        -   —CO-alkyl;        -   —S(O)₀₋₂-alkyl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-aryl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-substituted aryl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-heteroaryl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-substituted heteroaryl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-heterocyclyl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-substituted heterocyclyl;        -   -(alkyl)₀₋₁-N(R₆)₂;        -   -(alkyl)₀₋₁-NR₆—CO—O-alkyl;        -   -(alkyl)₀₋₁-NR₆—CO-alkyl;        -   -(alkyl)₀₋₁-NR₆—CO-aryl;        -   -(alkyl)₀₋₁-NR₆—CO-substituted aryl;        -   -(alkyl)₀₋₁-NR₆—CO-heteroaryl;        -   -(alkyl)₀₋₁-NR₆—CO-substituted heteroaryl;        -   —N₃;        -   -halogen;        -   -haloalkyl;        -   -haloalkoxy;        -   —CO-haloalkyl;        -   —CO-haloalkoxy;        -   —NO₂;        -   —CN;        -   —OH;        -   —SH; and in the case of alkyl, alkenyl, and heterocyclyl,            oxo;    -   R₂ is selected from the group consisting of:        -   -hydrogen;        -   -alkyl;        -   -alkenyl;        -   -aryl;        -   -substituted aryl;        -   -heteroaryl;        -   -substituted heteroaryl;        -   -alkyl-O-alkyl;        -   -alkyl-S-alkyl;        -   -alkyl-O-aryl;        -   -alkyl-S-aryl:        -   -alkyl-O-alkenyl;        -   -alkyl-S-alkenyl; and        -   -alkyl or alkenyl substituted by one or more substituents            selected        -   from the group consisting of:            -   —OH;            -   -halogen;            -   —N(R₆)₂;            -   —CO—N(R₆)₂;            -   —CS—N(R₆)₂;            -   —SO₂—N(R₆)₂;            -   —NR₆—CO—C₁₋₁₀ alkyl;            -   —NR₆—CS C₁₋₁₀ alkyl;            -   —NR₆—SO₂—C₁₋₁₀ alkyl;            -   —CO—C₁₋₁₀ alkyl;            -   —CO—O—C₁₋₁₀ alkyl;            -   —N₃;            -   -aryl;            -   -substituted aryl;            -   -heteroaryl;            -   -substituted heteroaryl;            -   -heterocyclyl;            -   -substituted heterocyclyl;            -   —CO-aryl;            -   —CO-(substituted aryl);            -   —CO-heteroaryl; and            -   —CO-(substituted heteroaryl);    -   R₃ and R₄ are independently selected from the group consisting        of hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino,        dialkylamino and alkylthio;    -   R₅ is H or C₁₋₁₀alkyl, or R₅ can join with X to form a ring; or        when R₁ is alkyl, R₅ and R₁ can join to form a ring;    -   each R₆ is independently H or C₁₋₁₀ alkyl;    -   or a pharmaceutically acceptable salt thereof.        Preparation of the Compounds

Compounds of the invention can be prepared according to Reaction SchemeI where R₁, R₂, R₃, R₄, R₅, X, Y and Z are as defined above, Bn isbenzyl and R′ is alkyl of one to four carbon atoms, perfluoroalkyl ofone to four carbon atoms, phenyl, or phenyl substituted by halogen oralkyl of one to four carbon atoms.

In step (1) of Reaction Scheme I a 3-nitropyridine-2,4-disulfonate ofFormula X is reacted with an amine of Formula R₁—Z—Y—N(R₅)—X—NH₂ toprovide a 3-nitro-4-aminopyridine-2-sulfonate of Formula XI. Due to thepresence of two sulfonate groups that could in principle be displaced,the reaction may provide a mixture of products that can be readilyseparated using conventional techniques such as column chromatography.The reaction is preferably carried out by adding the amine to a solutionof a compound of Formula X in a suitable solvent such as dichloromethanein the presence of a tertiary amine such as triethylamine. As thesulfonate group is a relatively facile leaving group, the reaction canbe run at a reduced temperature (0° C.) in order to decrease the amountof undesired 2-aminated and 2,4-diaminated side products.3-Nitropyridine-2,4-disulfonates are known and can be readily preparedusing known synthetic methods, see for example, Lindstom et al., U.S.Pat. No. 5,446,153 and the references cited therein.

In step (2) of Reaction Scheme I a 3-nitro-4-aminopyridine-2-sulfonateof Formula XI is reacted with dibenzylamine to provide a2-dibenzylamino-3-nitropyridin-4-amine of Formula XII. The reaction iscarried out by combining a compound of Formula XI, dibenzylamine, and atertiary amine such as triethylamine in an inert solvent such asbenzene, toluene or xylene and heating the resulting mixture.

In step (3) of Reaction Scheme I the nitro group of a2-dibenzylamino-3-nitropyridin-4-amine of Formula XII is reduced to anamino group. The reduction is preferably carried out using Ni₂B which isgenerated in situ from sodium borohydride and nickel chloride hydrate inmethanol. The reaction is preferably carried out at ambient temperature.

In step (4) of Reaction Scheme I a 2-dibenzylaminopyridine-3,4-diamineof Formula XIII is reacted with a carboxylic acid or an equivalentthereof to provide a 4-dibenzylamino-1H-imidazo[4,5-c]pyridine ofFormula XV. Suitable equivalents to carboxylic acid include orthoestersand 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will provide the desired R₂ substituent in acompound of Formula XV. For example, triethyl orthoformate will providea compound where R₂ is hydrogen and triethyl orthoacetate will provide acompound where R₂ is methyl. The reaction can be run in the absence ofsolvent or in an inert solvent such as toluene. The reaction is run withsufficient heating to drive off any alcohol or water formed as abyproduct of the reaction. Optionally a catlayst such as pyridinehydrochloride can be included.

Alternatively, a compound of Formula XV can be prepared in two steps by(a) reacting a diamine of Formula XIII with an acyl halide of formulaR₂C(O)Cl or R₂C(O)Br to provide a compound of Formula XIV and then (b)cyclizing. In step (4a) the acyl halide is added to a solution of thediamine in an inert solvent such as acetonitrile, pyridine ordichloromethane. The reaction can be carried out at ambient temperature.In step (4b) the product of step (4a) is heated in an alcoholic solventin the presence of a base. Preferably the product of step (4a) isrefluxed in ethanol in the presence of an excess of triethylamine orheated with methanolic ammonia. Alternatively step (4b) can be carriedout by heating the product of step (4a) in pyridine. If step (4a) wascarried out in pyridine, step (4b) can be carried out by heating thereaction mixture after analysis indicates that step (4a) is complete.

In step (5) of Reaction Scheme I a4-dibenzylamino-1H-imidazo[4,5-c]pyridine of Formula XV ishydrogenolyzed to provide the 4-amino-1H-imidazo[4,5-c]pyridine ofFormula I. Preferably the compound of Formula XV is heated in formicacid in the presence of palladium hydroxide on carbon. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Compounds of the invention can be prepared according to Reaction SchemeII where R₁, R₂, R₃, R₄, R₅ and X are as defined above, Bn is benzyl,BOC is tert-butoxycarbonyl and W is O or S.

In step (1) of Reaction Scheme II the amine protecting groups of a1H-imidazo[4,5-c]pyridine of Formula XVI are removed to provide a1H-imidazo[4,5-c]pyridine of Formula II. Preferably a solution of acompound of Formula XVI in a suitable solvent such as dichloromethane istreated with triflic acid at ambient temperature. Compounds of FormulaXVI can be prepared using the synthetic method described in ReactionScheme I. In step (1) a 2,4-disulfonate of Formula X is reacted with anamine of formula BOC—NR₅—X—NH₂. Steps (2)-(4) are then carried out asdescribed above to provide a compound of Formula XVI which is a subgenusof Formula XV.

In step (2a) of Reaction Scheme II, a 1H-imidazo[4,5-c]pyridine ofFormula II is reacted with an acid chloride of formula R₁—C(O)Cl or anacid anhydride of formula R₁—C(O)OC(O)—R₁ to provide a1H-imidazo[4,5-c]pyridin-1-yl amide of Formula XVII. The reaction ispreferably carried out by adding the acid chloride or acid anhydride toa solution of a compound of Formula II in a suitable solvent such asdichloromethane or acetonitrile in the presence of a base such astriethylamine. The reaction can be run at a reduced temperature (0° C.)or at ambient temperature. The product or a pharmaceutically acceptablesalt thereof can be isolated using conventional methods.

In step (2b) of Reaction Scheme II, a 1H-imidazo[4,5-c]pyridine ofFormula II is reacted with an isocyanate of formula R₁—N═C═O or with anisothiocyanate of formula R₁—N═C═S to provide a1H-imidazo[4,5-c]pyridin-1-yl urea or thiourea of Formula XVIII. Thereaction is preferably carried out by adding the isocyanate orisothiocyanate to a solution of a compound of Formula II in a suitablesolvent such as dichloromethane at a reduced temperature (0° C.). Theproduct or a pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

In step (2c) of Reaction Scheme II, a 1H-imidazo[4,5-c]pyridine ofFormula II is reacted with a sulfonyl chloride of formula R₁—S(O)₂Cl ora sulfonic anhydride of formula R₁—S(O)₂OS(O)₂—R₁, to provide a1H-imidazo[4,5-c]pyridin-1-yl sulfonamide of Formula XIX which is asubgenus of Formula I. The reaction is preferably carried out by addingthe sulfonyl chloride or sulfonic anhydride to a solution of a compoundof Formula II in a suitable solvent such as dichloromethane in thepresence of a base such as triethylamine. The reaction can be run at areduced temperature (0° C.) or at ambient temperature. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Compounds of the invention can be prepared according to Reaction SchemeIII where R₁, R₂, R₃, R₄, R₅, R₆ and X, are as defined above.

In step (1) of Reaction Scheme III a 1H-imidazo[4,5-c]pyridine ofFormula II is reacted with a sulfamoyl chloride of formulaR₁—N(R₆)S(O)₂Cl to provide a 1H-imidazo[4,5-c]pyridin-1-yl sulfamide ofFormula XXI which is a subgenus of Formula I. Preferably the sulfamoylchloride is added to a solution of the compound of Formula II in asuitable solvent such as 1,2-dichloroethane in the presence of a basesuch as triethylamine. The reaction can be run at an elevatedtemperature. The product or a pharmaceutically acceptable salt thereofcan be isolated using conventional methods.

Alternatively a sulfamide of Formula XXI can be prepared in two steps by(a) reacting a 1H-imidazo[4,5-c]pyridine of Formula II with sulfurylchloride to generate in situ a sulfamoyl chloride of Formula XX and then(b) reacting the sulfamoyl choride with an amine of formula R₁—N(R₆)H.In step (1a) the reaction can be carried out by adding a solution ofsulfuryl chloride in dichloromethane to a solution of a compound ofFormula II in the presence of 1 equivalent of 4-(dimethylamino)pyridine.The reaction is preferably carried out at a reduced temperature (−78°C.). Optionally, after the addition is complete the reaction mixture canbe allowed to warm to ambient temperature. In step (1b) a solutioncontaining 2 equivalents of R₁—N(R₆)H and 2 equivalents of triethylaminein dichloromethane is added to the reaction mixture from step (1a). Thereaction is preferably carried out at a reduced temperature (−78° C.).The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

Compounds of the invention can be prepared according to Reaction SchemeIV where R₁, R₂, R₃, R₄, R₅, and X are as defined above and BOC istert-butoxycarbonyl.

In step (1) of Reaction Scheme IV a 2,4-dihydroxy-3-nitropyridine ofFormula XXII is chlorinated using conventional chlorinating agents toprovide a 2,4-dichloro-3-nitropyridine of Formula XXIII. Preferably acompound of Formula XXII is combined with phosphorous oxychloride andheated. Many 2,4-dihydroxy-3-nitropyridines of Formula XXII are knownand others can be readily prepared using known synthetic methods, seefor example, Lindstom et al., U.S. Pat. No. 5,446,153 and the referencescited therein.

In step (2) of Reaction Scheme IV a 2,4-dichloro-3-nitropyridine ofFormula XXIII is reacted with an amine of formula BOC—NR₅—X—NH₂ toprovide a 2-chloro-3-nitropyridine of Formula XXIV. The reaction ispreferably carried out by adding the amine to a solution of a compoundof Formula XXIII in a suitable solvent such as N,N-dimethylformamide inthe presence of a tertiary amine such as triethylamine, and optionallyheating.

In step (3) of Reaction Scheme IV a 2-chloro-3-nitropyridine of FormulaXXIV is reacted with phenol to provide a 3-nitro-2-phenoxypyridine ofFormula XXV. Phenol is reacted with sodium hydride in a suitable solventsuch as diglyme or tetrahydrofuran to form the phenoxide. The phenoxideis then reacted at ambient temperature, or optionally at an elevatedtemperature, with a compound of Formula XXIV.

In step (4) of Reaction Scheme IV a 3-nitro-2-phenoxypyridine of FormulaXXV is reduced to provide a 3-amino-2-phenoxypyridine of Formula XXVI.Preferably, the reduction is carried out using a conventionalheterogeneous hydrogenation catalyst such as platinum on carbon orpalladium on carbon. The reaction can conveniently be carried out on aParr apparatus in a suitable solvent such as isopropyl alcohol, tolueneor mixtures thereof.

In step (5) of Reaction Scheme IV a 3-amino-2-phenoxypyridine of FormulaXXVI is reacted with a carboxylic acid or an equivalent thereof toprovide a 4-phenoxy-1H-imidazo[4,5-c]pyridine of Formula IV. Suitableequivalents to carboxylic acid include orthoesters, and1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will provide the desired R₂ substituent in acompound of Formula IV. For example, triethyl orthoformate will providea compound where R₂ is hydrogen and trimethyl orthovalerate will providea compound where R₂ is butyl. The reaction can be run in the absence ofsolvent or in an inert solvent such as toluene. The reaction is run withsufficient heating to drive off any alcohol or water formed as abyproduct of the reaction. Optionally a catalyst such as pyridinehydrochloride can be included.

Alternatively, step (5) can be carried out by (i) reacting a compound ofFormula XXVI with an acyl halide of formula R₂C(O)Cl or R₂C(O)Br andthen (ii) cyclizing. In part (i) the acyl halide is added to a solutionof a compound of Formula XXVI in an inert solvent such as acetonitrile,pyridine or dichloromethane. The reaction can be carried out at ambienttemperature. Optionally a catalyst such as pyridine hydrochloride can beincluded. In part (ii) the product of part (i) is heated in pyridine. Ifstep (i) is run in pyridine, then the two steps can combined into asingle step.

In step (6) of Reaction Scheme IV the BOC group is removed from acompound of Formula IV to provide 4-phenoxy-1H-imidazo[4,5-c]pyridine ofFormula V. Preferably a solution of a compound of Formula IV in asuitable solvent such as dichloromethane is treated with trifluoroaceticacid or hydrochloric acid at a reduced temperature.

In step (7) of Reaction Scheme IV a 4-phenoxy-1H-imidazo[4,5-c]pyridineof Formula V is converted to a 4-phenoxy-1H-imidazo[4,5-c]pyridin-1-ylsulfonamide of Formula VI using the method of step (2c) of ReactionScheme II.

In step (8) of Reaction Scheme IV4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl sulfonamide of Formula VI isaminated to provide a 4-amino-1H-imidazo[4,5-c]pyridin-1-yl sulfonamideof Formula XIX. The reaction can be carried out by combining a compoundof Formula VI with ammonium acetate in a sealed tube and heating (˜150°C.). The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

Compounds of the invention can be prepared according to Reaction SchemeV where R₁, R₂, R₃, R₄, R₅, and X are as defined above and BOC istert-butoxycarbonyl.

In step (1) of Reaction Scheme V, a 4-phenoxy-1H-imidazo[4,5-c]pyridineof Formula IV is aminated to provide anN-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)acetamide of Formula XXVIII.Preferably a compound of Formula IV is combined with ammonium acetate atan elevated temperature (140-160° C.). Optionally, the reaction can berun in a pressure vessel.

In step (2) of Reaction Scheme V, anN-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)acetamide of Formula XXVIII ishydrolyzed under acidic conditions to provide a1H-imidazo[4,5-c]pyridin-4-amine of Formula II. Preferably, a compoundof Formula XXVIII is combined with hydrochloric acid/ethanol and heated.

In step (3) of Reaction Scheme V, a 1H-imidazo[4,5-c]pyridin-4-amine ofFormula II is converted using conventional methods to a sulfonamide ofFormula XIX, which is a subgenus of Formula I. The reaction can becarried out as described in step (2c) of Reaction Scheme II. The productor a pharmaceutically acceptable salt thereof can be isolated usingconventional methods.

The invention also provides novel compounds useful as intermediates inthe synthesis of the compounds of Formula I. These intermediates havestructural Formulas (II)-(VI) described in more detail below.

One class of intermediate compounds has Formula (II):

wherein:

-   -   X is alkylene or alkenylene;    -   R₂ is selected from the group consisting of:        -   -hydrogen;        -   -alkyl;        -   -alkenyl;        -   -alkyl-O-alkyl;        -   -alkyl-S-alkyl;        -   -alkyl-O-aryl;        -   -alkyl-S-aryl;        -   -alkyl-O-alkenyl;        -   -alkyl-S-alkenyl; and        -   -alkyl or alkenyl substituted by one or more substituents            selected from the group consisting of:            -   —OH;            -   -halogen;            -   —N(R₆)₂;            -   —CO—N(R₆)₂;            -   —CS—N(R₆)₂;            -   —SO₂—N(R₆)₂;            -   —NR₆—CO—C₁₋₁₀ alkyl;            -   —NR₆—CS—C₁₋₁₀ alkyl;            -   —NR₆—SO₂—C₁₋₁₀ alkyl;            -   —CO—C₁₋₁₀ alkyl;            -   —CO—O—C₁₋₁₀ alkyl;            -   —N₃;            -   -aryl;            -   -heteroaryl;            -   -heterocyclyl;            -   —CO-aryl; and            -   —CO-heteroaryl;    -   R₃ and R₄ are independently selected from the group consisting        of hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino,        dialkylamino and alkylthio; and    -   R₅ is H or C₁₋₁₀ alkyl;    -   each R₆ is independently H or C₁₋₁₀ alkyl; or a pharmaceutically        acceptable salt thereof.

Another class of intermediates has the Formula III:

wherein:

-   -   Q is NO₂ or NH₂;    -   X is alkylene or alkenylene;    -   R₃ and R₄ are independently selected from the group consisting        of hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino,        dialkylamino and alkylthio; and    -   R₅ is H or C₁₋₁₀ alkyl; or a pharmaceutically acceptable salt        thereof.

Another class of intermediates has the Formula (IV):

wherein:

-   -   X is alkylene or alkenylene;    -   R₂ is selected from the group consisting of:        -   -hydrogen;        -   -alkyl;        -   -alkenyl;        -   -alkyl-O-alkyl;        -   -alkyl-S-alkyl;        -   -alkyl-O-aryl;        -   -alkyl-S-aryl;        -   -alkyl-O-alkenyl;        -   -alkyl-S-alkenyl; and        -   -alkyl or alkenyl substituted by one or more substituents            selected from the group consisting of:            -   —OH;            -   -halogen;            -   —N(R₆)₂;            -   —CO—N(R₆)₂;            -   —CS—N(R₆)₂;            -   —SO₂—N(R₆)₂;            -   —NR₆—CO—C₁₋₁₀ alkyl;            -   —NR₆—CS—C₁₋₁₀ alkyl;            -   —NR₆—SO₂—C₁₋₁₀ alkyl;            -   —CO—C₁₋₁₀ alkyl;            -   —CO—O—C₁₋₁₀ alkyl;            -   —N₃;            -   -aryl;            -   -heteroaryl;            -   -heterocyclyl;            -   —CO-aryl; and            -   —CO-heteroaryl;    -   R₃ and R₄ are independently selected from the group consisting        of hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino,        dialkylamino and alkylthio; and    -   R₅is H or C₁₋₁₀ alkyl;    -   each R₆ is independently H or C₁₋₁₀ alkyl; or a pharmaceutically        acceptable salt thereof.

Another class of intermediates has the Formula (V):

wherein:

-   -   X is alkylene or alkenylene;    -   R₂ is selected from the group consisting of:        -   -hydrogen;        -   -alkyl;        -   -alkenyl;        -   -alkyl-O-alkyl;        -   -alkyl-S-alkyl;        -   -alkyl-O-aryl;        -   -alkyl-S-aryl;        -   -alkyl-O-alkenyl;        -   -alkyl-S-alkenyl; and        -   -alkyl or alkenyl substituted by one or more substituents            selected from the group consisting of:            -   —OH;            -   -halogen;            -   —N(R₆)₂;            -   —CO—N(R₆)₂;            -   —CS—N(R₆)₂;            -   —SO₂—N(R₆)₂;            -   —NR₆—CO—C₁₋₁₀ alkyl;            -   —NR₆—CS—C₁₋₁₀ alkyl;            -   —NR₆—SO₂—C₁₋₁₀ alkyl;            -   —CO—C₁₋₁₀ alkyl;            -   —CO—O—C₁₋₁₀ alkyl;            -   —N₃;            -   -aryl;            -   -heteroaryl;            -   -heterocyclyl;            -   —CO-aryl; and            -   —CO-heteroaryl;    -   R₃ and R₄ are independently selected from the group consisting        of hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino,        dialkylamino and alkylthio; and    -   R₅ is H or C₁₋₁₀ alkyl;    -   each R₆ is independently H or C₁₋₁₀ alkyl; or a pharmaceutically        acceptable salt thereof.

Another class of intermediates has the Formula (VI):

wherein:

-   -   X is alkylene or alkenylene;    -   R₁ is aryl, heteroaryl, heterocyclyl, C₁₋₂₀ alkyl or C₂₋₂₀        alkenyl, each of which may be unsubstituted or substituted by        one or more substituents independently selected from the group        consisting of:        -   -alkyl;        -   -alkenyl;        -   -aryl;        -   -heteroaryl;        -   -heterocyclyl;        -   -substituted cycloalkyl;        -   —O-alkyl;        -   —O-(alkyl)₀₋₁-aryl;        -   —O-(alkyl)₀₋₁-heteroaryl;        -   —O-(alkyl)₀₋₁-heterocyclyl;        -   —COOH;        -   —CO—O-alkyl;        -   —CO-alkyl;        -   S(O)₀₋₂-alkyl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-aryl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-heteroaryl;        -   —S(O)₀₋₂-(alkyl)₀₋₁-heterocyclyl;        -   -(alkyl)₀₋₁-N(R₆)₂;        -   -(alkyl)₀₋₁-NR₆—CO—O-alkyl;        -   -(alkyl)₀₋₁-NR₆—CO-alkyl;        -   -(alkyl)₀₋₁-NR₆—CO-aryl;        -   -(alkyl)₀₋₁-NR₆—CO-heteroaryl;        -   —N₃;        -   -halogen;        -   -haloalkyl;        -   -haloalkoxy;        -   —CO-haloalkyl;        -   —CO-haloalkoxy;        -   —NO₂;        -   —CN;        -   —OH;        -   —SH; and in the case of alkyl, alkenyl, and heterocyclyl,            oxo;    -   R₂ is selected from the group consisting of:        -   -hydrogen;        -   -alkyl;        -   -alkenyl;        -   -alkyl-O-alkyl;        -   -alkyl-S-alkyl;        -   -alkyl-O-aryl;        -   -alkyl-S-aryl;        -   -alkyl-O-alkenyl;        -   -alkyl-S-alkenyl; and        -   -alkyl or alkenyl substituted by one or more substituents            selected from the group consisting of:            -   —OH;            -   -halogen;            -   —N(R₆)₂;            -   —CO—N(R₆)₂;            -   —CS—N(R₆)₂;            -   —SO₂—N(R₆)₂;            -   —NR₆—CO—C₁₋₁₀ alkyl;            -   —NR₆—CS—C₁₋₁₀ alkyl;            -   —NR₆—SO₂—C₁₋₁₀ alkyl;            -   —CO—C₁₋₁₀ alkyl;            -   —CO—O—C₁₋₁₀ alkyl;            -   —N₃;            -   -aryl;            -   -heteroaryl;            -   -heterocyclyl;            -   —CO-aryl; and            -   —CO-heteroaryl;    -   R₃ and R₄ are independently selected from the group consisting        of hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino,        dialkylamino and alkylthio; and    -   each R₅ is independently H or C₁₋₁₀ alkyl; or R₅ can join with X        to form a ring;    -   each R₆ is independently H or C₁₋₁₀ alkyl; or a pharmaceutically        acceptable salt thereof.

As used herein, the terms “alkyl”, “alkenyl” and the prefix “alk-” areinclusive of both straight chain and branched chain groups and of cyclicgroups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified,these groups contain from 1 to 20 carbon atoms, with alkenyl groupscontaining from 2 to 20 carbon atoms. Preferred groups have a total ofup to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic andpreferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groupsinclude cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,adamantly, norbornane, and norbornene.

The term “haloalkyl” is inclusive of groups that are substituted by oneor more halogen atoms, including perfluorinated groups. This is alsotrue of groups that include the prefix “halo-”. Examples of suitablehaloalkyl groups are chloromethyl, trifluoromethyl, and the like.

The term “aryl” as used herein includes carbocyclic aromatic rings orring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl,tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl,benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl,quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl,purinyl, quinazolinyl, and so on.

“Heterocyclyl” includes non-aromatic rings or ring systems that containat least one ring hetero atom (e.g., O, S, N) and includes all of thefully saturated and partially unsaturated derivatives of the abovementioned heteroaryl groups. Exemplary heterocyclic groups includepyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, andimidazolidinyl.

The aryl, heteroaryl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro,hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio,arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio,heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino,heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl,alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy,arylcarbonythio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino,arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino,arylcarbonylamino, arylalkylcarbonylamino, arylcarbonylaminoalkyl,heteroarylcarbonylamino, heteroarylalkycarbonylamino,alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino,arylalkylsulfonylamino, heteroarylsulfonylamino,heteroarylalkylsulfonylamino, alkylaminocarbonylamino,alkenylaminocarbonylamino, arylaminocarbonylamino,arylalkylaminocarbonylamino, heteroarylaminocarbonylamino,heteroarylalkylaminocarbonylamino and, in the case of heterocyclyl, oxo.If other groups are described as being “substituted” or “optionallysubstituted”, then those groups can also be substituted by one or moreof the above enumerated substituents.

Certain substituents are generally preferred. For example, Z ispreferably a bond or —NR₅—; and R₁ is preferably C₁₋₄ alkyl, aryl, orsubstituted aryl. Preferred R₂ groups include alkyl groups having 1 to 4carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, isobutyl, and tert-butyl), methoxyethyl, ethoxymethyl, andcyclopropylmethyl. R₃ and R₄ are preferably methyl. One or more of thesepreferred substitutents, if present, can be present in the compounds ofthe invention in any combination.

The invention is inclusive of the compounds described herein in any oftheir pharmaceutically acceptable forms, including isomers such asdiastereomers and enantiomers, salts, solvates, polymorphs, and thelike. In particular, if a compound is optically active, the inventionspecifically includes each of the compound's enantiomers as well asracemic mixtures of the enantiomers.

Pharmaceutical Compositions and Biological Activity

Pharmaceutical compositions of the invention contain a therapeuticallyeffective amount of a compound of the invention as described above incombination with a pharmaceutically acceptable carrier.

The term “a therapeutically effective amount” means an amount of thecompound sufficient to induce a therapeutic effect, such as cytokineinduction, antitumor activity, and/or antiviral activity. Although theexact amount of active compound used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound, thenature of the carrier, and the intended dosing regimen, it isanticipated that the compositions of the invention will containsufficient active ingredient to provide a dose of about 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of thecompound to the subject. Any of the conventional dosage forms may beused, such as tablets, lozenges, parenteral formulations, syrups,creams, ointments, aerosol formulations, transdermal patches,transmucosal patches and the like.

The compounds of the invention can be administered as the singletherapeutic agent in the treatment regimen, or the compounds of theinvention may be administered in combination with one another or withother active agents, including additional immune response modifiers,antivirals, antibiotics, antibodies, proteins, peptides,oligonucleotides, etc.

The compounds of the invention have been shown to induce the productionof certain cytokines in experiments performed according to the tests setforth below. These results indicate that the compounds are useful asimmune response modifiers that can modulate the immune response in anumber of different ways, rendering them useful in the treatment of avariety of disorders.

Cytokines whose production may be induced by the administration ofcompounds according to the invention generally include interferon-α(IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 andIL-12, and a variety of other cytokines. Among other effects, these andother cytokines can inhibit virus production and tumor cell growth,making the compounds useful in the treatment of viral diseases andtumors. Accordingly, the invention provides a method of inducingcytokine biosynthesis in an animal comprising administering an effectiveamount of a compound or composition of the invention to the animal.

Certain compounds of the invention have been found to preferentiallyinduce the expression of IFN-α in a population of hematopoietic cellssuch as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells(precursor dendritic cell-type 2) without concomitant production ofsignificant levels of inflammatory cytokines.

In addition to the ability to induce the production of cytokines, thecompounds of the invention affect other aspects of the innate immuneresponse. For example, natural killer cell activity may be stimulated,an effect that may be due to cytokine induction. The compounds may alsoactivate macrophages, which in turn stimulates secretion of nitric oxideand the production of additional cytokines. Further, the compounds maycause proliferation and differentiation of B-lymphocytes.

Compounds of the invention also have an effect on the acquired immuneresponse. For example, although there is not believed to be any directeffect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th1) cytokine IFN-γ is inducedindirectly and the production of the T helper type 2 (Th2) cytokinesIL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.This activity means that the compounds are useful in the treatment ofdiseases where upregulation of the Th1 response and/or downregulation ofthe Th2 response is desired. In view of the ability of compounds of theinvention to inhibit the Th2 immune response, the compounds are expectedto be useful in the treatment of atopic diseases, e.g., atopicdermatitis, asthma, allergy, allergic rhinitis; systemic lupuserythematosis; as a vaccine adjuvant; and possibly as a treatment forrecurrent fungal diseases and chlamydia.

The immune response modifying effects of the compounds make them usefulin the treatment of a wide variety of conditions. Because of theirability to induce the production of cytokines such as IFN-α and/orTNF-α, the compounds are particularly useful in the treatment of viraldiseases and tumors. This immunomodulating activity suggests thatcompounds of the invention are useful in treating diseases such as, butnot limited to, viral diseases including genital warts; common warts;plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I andType II; molluscum contagiosum; variola, particularly variola major;HIV; CMV; VZV; rhinovirus; adenovirus; coronavirus; influenza; andpara-influenza; intraepithelial neoplasias such as cervicalintraepithelial neoplasia; human papillomavirus (HPV) and associatedneoplasias; fungal diseases, e.g. candida, aspergillus, and cryptococcalmeningitis; neoplastic diseases, e.g., basal cell carcinoma, hairy cellleukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cellcarcinoma, myelogenous leukemia, multiple myeloma, melanoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers;parasitic diseases, e.g. pneumocystis carnii, cryptosporidiosis,histoplasmosis, toxoplasmosis, trypanosome infection, and leishmaniasis;and bacterial infections, e.g., tuberculosis, and mycobacterium avium.Additional diseases or conditions that can be treated using thecompounds of the invention include actinic keratosis; eczema;eosinophilia; essential thrombocythaemia; leprosy; multiple sclerosis;Ommen's syndrome; discoid lupus; Bowen's disease; Bowenoid papulosis;alopecia areata; the inhibition of Keloid formation after surgery andother types of post-surgical scars. In addition, these compounds couldenhance or stimulate the healing of wounds, including chronic wounds.The compounds may be useful for treating the opportunistic infectionsand tumors that occur after suppression of cell mediated immunity in,for example, transplant patients, cancer patients and HIV patients.

An amount of a compound effective to induce cytokine biosynthesis is anamount sufficient to cause one or more cell types, such as monocytes,macrophages, dendritic cells and B-cells to produce an amount of one ormore cytokines such as, for example, IFN-α, TNF-α, IL-1, IL-6, IL-10 andIL-12 that is increased over the background level of such cytokines. Theprecise amount will vary according to factors known in the art but isexpected to be a dose of about 100 ng/kg to about 50 mg/kg, preferablyabout 10 μg/kg to about 5 mg/kg. The invention also provides a method oftreating a viral infection in an animal and a method of treating aneoplastic disease in an animal comprising administering an effectiveamount of a compound or composition of the invention to the animal. Anamount effective to treat or inhibit a viral infection is an amount thatwill cause a reduction in one or more of the manifestations of viralinfection, such as viral lesions, viral load, rate of virus production,and mortality as compared to untreated control animals. The preciseamount that is effective for such treatment will vary according tofactors known in the art but is expected to be a dose of about 100 ng/kgto about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. An amountof a compound effective to treat a neoplastic condition is an amountthat will cause a reduction in tumor size or in the number of tumorfoci. Again, the precise amount will vary according to factors known inthe art but is expected to be a dose of about 100 ng/kg to about 50mg/kg, preferably about 10 μg/kg to about 5 mg/kg.

The invention is further described by the following examples, which areprovided for illustration only and are not intended to be limiting inany way.

In the examples below some of the compounds were purified by preparativehigh performance liquid chromatography using a Waters Fraction Lynxautomated purification system. The prep HPLC fractions were analyzedusing a Micromass LC-TOFMS and the appropriate fractions were combinedand centrifuge evaporated to provide the trifluoroacetate salt of thedesired compound. Column: Phenomenex Luna C18(2), 21.2×50 mm, 10 micronparticle size, 100 Å pore; flow rate: 25 mL/min.; non-linear gradientelution from 5-95% B in 12 min, then hold at 95% B for 2 min., where Ais 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacticacid/acetonitrile; fraction collection by mass-selective triggering.

EXAMPLE 1N-[4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]benzamide

Part A

Triethylamine (16.8 mL, 123.8 mmol) was added to a suspension of4-hydroxy-5,6-dimethyl-3-nitro-2(1H)-pyridone (7.6 g, 41.2 mmol) indichloromethane (200 mL). The resulting mixture was cooled in an icebath. Triflic anhydride (13.7 mL, 82.5 mmol) was added and the reactionmixture was stirred for 30 minutes.Mono-tert-butoxycarbonyl-1,4-butyldiamine (7.6 g, 41.2 mmol) was addedin a single portion and the reaction mixture was allowed to warm toambient temperature. After 1 hour the reaction mixture was washed withaqueous 1% sodium carbonate (2×100 mL), dried over magnesium sulfate andthen concentrated under reduced pressure to provide crude product. Thismaterial was dissolved in dichloromethane and loaded onto a layer ofsilica gel. The silica gel was eluted first with dichloromethane toremove some impurities and then with 2-5% ethyl acetate indichloromethane to recover the desired product. The fractions containingproduct were combined and then concentrated under reduced pressure toprovide 12 g of4-({4-[(tert-butoxycarbonyl)amino]butyl}amino)-5,6-dimethyl-3-nitropyridin-2-yltrifluoromethanesulfonate as a light yellow oil.

Part B

The material from Part A was combined with triethylamine (2.5 g, 24.7mmol), dibenzylamine (4.8 g, 24.7 mmol), and toluene (150 mL) and thenheated at reflux for 4 hours. The reaction mixture was washed withaqueous 1% sodium carbonate and then concentrated under reduced pressureto provide crude product. This material was dissolved in dichloromethaneand loaded onto silica gel. The silica gel was eluted with 2-20% ethylacetate in dichloromethane. The fractions containing product werecombined and then concentrated under reduced pressure to provide ˜13 gof tert-butyl4-{[2-(dibenzylamino)-5,6-dimethyl-3-nitropyridin-4-yl]amino}butylcarbamate.

Part C

Sodium borohydride (1.4 g, 36 mnuol) was slowly added to a solution ofnickel chloride hydrate (2.9 g, 12.3 mmol) in methanol and the resultingmixture was stirred for 30 minutes. A solution of the material from PartB in methanol was added in a single portion. Sodium borohydride wasslowly added until the foaming was colorless. The reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure. Theresulting residue was combined with dichloromethane and the mixture wasfiltered to remove salts. The filtrate was concentrated under reducedpressure to provide ˜12 g of tert-butyl4-{[3-amino-2-(dibenzylamino)-5,6-dimethylpyridin-4-yl]amino}butylcarbamate.

Part D

Valeryl chloride (3 mL, 24.7 mmol) was added to a solution of thematerial from Part C in acetonitrile (200 mL). The reaction mixture wasstirred at ambient temperature. The reaction mixture was concentratedunder reduced pressure. The residue was combined with ethanol andtriethylamine (5 g, 49 mmol.). The reaction mixture was heated at refluxovernight and then concentrated under reduced pressure. The resultingresidue was partitioned between dichloromethane and water. Thedichloromethane layer was separated and then loaded onto a silica gelcolumn. The column was eluted with 9:90:1 ethyl acetate:dichloromethane:methanol. The fractions containing product were combined and thenconcentrated under reduced pressure to provide 6.5 g of tert-butyl4-[2-butyl-4-(dibenzylamino)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamateas an oil.

Part E

Triflic acid (16 g, 107 mmol) was added to a solution of the materialfrom Part D (6.5 g, 11.4 mmol) in dichloromethane (250 mL). Theresulting mixture was stirred overnight. Ammonium hydroxide (50 mL) andwater (100 mL) were added and the resulting mixture was stirred for 30minutes. The layers were separated and the aqueous fraction wasextracted with dichloromethane (100 mL). The organic fractions werecombined, washed with 1% aqueous sodium carbonate, washed with brine andconcentrated under reduced pressure. The residue was combined withmethanol (30 mL), stirred for 30 minutes and filtered. The filtrate wasconcentrated under reduced pressure and the resulting residue wascombined with 1% aqueous sodium carbonate and stirred. The mixture wasextracted with hexane to remove organic impurities. The aqueous layercontained an insoluble oil that was extracted with dichloromethane. Theorganic layer was combined with magnesium sulfate, stirred for 5 minutesand filtered. The filtrate was concentrated under reduced pressure toprovide a solid which was recrystallized from toluene to provide 1 g of1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine.

Part F

Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine(150 mg, 0.5 mmol) in dichloromethane (150 mL). The reaction mixture wascooled in an ice bath. Benzoyl chloride (0.07 mL, 0.5 mmol) was addedand the reaction mixture was removed from the ice bath. The reactionmixture was washed twice with water and then concentrated under reducedpressure. The resulting residue was purified by flash chromatographyeluting with 10% methanol in dichloromethane to provide an oily brownmaterial. This material was dissolved in a minimum amount of isopropanoland then ethanesulfonic acid (55 mg, 0.5 mmol) was added with stirring.The reaction mixture was stirred at ambient temperature for ˜1 hour andthen heated briefly in a sand bath until it became homogeneous. Thesolution was allowed to cool to ambient temperature and then was chilledin an ice bath. The resulting precipitate was isolated by filtration toprovide 111 mg ofN-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]benzamideas a crystalline solid, m.p. 127.8-128.8° C.

Analysis: Calculated for C₂₃H₃₁N₅O: % C, 70.20; % H, 7.94; % N, 17.80;Found: % C, 69.82; % H, 7.70; % N, 17.68.

EXAMPLE 2N-[4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide

Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine(150 mg, 0.5 mmol) in dichloromethane (160 mL). The reaction mixture wascooled in an ice bath. Methanesulfonic anhydride (90 mg, 0.5 mmol) wasadded and the reaction mixture was removed from the ice bath. Thereaction mixture was stirred for 35 minutes. The reaction mixture waswashed three times with water, concentrated under reduced pressure, andtriturated with a minimum volume of methyl acetate. The resultingcrystalline solid was isolated by filtration and then dried in anAbderhalden drying apparatus to provide 94 mg ofN-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide,m.p. 130.0-130.5° C.

Analysis: Calculated for C₁₇H₂₉N₅O₂S: % C, 55.56; % H, 7.95; % N, 19.06;Found: % C, 55.37; % H, 7.89; % N, 18.03.

EXAMPLE 3N-[4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-fluorobenzenesulfonamideHydrate

Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine(150 mg, 0.5 mmol) in dichloromethane (150 mL). The reaction mixture wascooled in an ice bath. 4-Fluorobenzenesulfonyl chloride (113 mg, 0.5mmol) was added and the reaction mixture was removed from the ice bath.The reaction mixture was stirred at ambient temperature for 48 hours.The reaction mixture was washed with water (2×150 mL) and thenconcentrated under reduced pressure. The resulting residue wasrecrystallized from methyl acetate and then dried in an Abderhaldendrying apparatus to provide 50 mg ofN-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-fluorobenzenesulfonamidehydrate as a white crystalline solid, m.p. 133.1-133.7° C.

Analysis: Calculated for C₂₂H₃₀FN₅O₂S.H₂O: % C, 56.75; % H, 6.93; % N,15.04; Found: % C, 56.99; % H, 6.58; % N, 15.24.

EXAMPLE 4N-[4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N′-phenylurea

Phenylisocyanate (0.056 mL, 0.5 mmol) was added to a chilled solution ofof1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine(150 mg, 0.5 mmol) in dichloromethane (150 mL). The ice bath wasremoved. A white precipitate formed after 5 minutes. The reactionmixture was allowed to stir for 30 minutes and then it was concentratedunder reduced pressure to provide an off-white crystalline solid. Thismaterial was isolated by filtration using a small amount of diethylether to transfer the material to the filter and then dried in anAbderhalden drying apparatus to provide 185 mg ofN-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N′-phenylurea,m.p. 195.8-196.8° C.

Analysis: Calculated for C₂₃H₃₂N₆O: % C, 67.62; % H, 7.89; % N, 20.57;Found: % C, 66.84; % H, 7.71; % N, 20.54.

EXAMPLE 5N-[4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N′-phenylthioureaHydrate

Using the method of Example 4,1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine(100 mg, 0.35 mmol) was reacted with phenylisothiocyanate (0.041 mL,0.35 mmol) to provide 97 mg ofN-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N′-phenylthioureahydrate as a white crystalline solid, m.p. 160.0-160.8° C.

Analysis: Calculated for C₂₃H₃₂N₆S.H₂O: % C, 62.41; % H, 7.74; % N,18.99; Found: % C, 62.39; % H, 7.47; %, 18.52.

EXAMPLE 6N′-[4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N,N-dimethylsulfamide

Triethylamine (0.031 mL, 0.23 mmol) was added to a solution of1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine(67 mg, 0.23 mmol) in dichloromethane (45 mL). The reaction mixture wascooled in an ice bath. Dimethylsulfamoyl chloride (0.025 mL, 0.23 mmol)was added. The reaction mixture was removed from the ice bath. Thereaction mixture was allowed to stir at ambient temperature for ˜113hours. Analysis by HPLC indicated that the reaction was not complete.The dichloromethane was removed under reduced pressure.1,2-Dichloroethane (50 mL) was added and the reaction mixture was heatedto 60° C. After 3 hours, more dimethylsulfamoyl chloride (2.5 μL) wasadded and heating was continued. After 22 hours the reaction temperaturewas raised to reflux and the reaction mixture was refluxed for 100hours. The reaction mixture was extracted twice with water. The aqueousfractions were combined and concentrated under reduced pressure. Theresulting residue was recrystallized from methyl acetate to provide 10mg ofN′-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N,N-dimethylsulfamideas an off-white crystalline solid, m.p. 129.5-131° C. M/Z=397.1 (M+H)⁺.

EXAMPLE 7N-[4-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide

Part A

A mixture of 5,6-dimethyl-3-nitropyridine-2,4-diol (60.0 g, 326 mmol)and phosphorus oxychloride (600 mL) was heated at reflux for 2 hrs. Thereaction mixture was concentrated under reduced pressure. The resultingresidue was combined with ethyl acetate (300 mL) and then filtered. Thefiltrate was washed with aqueous sodium bicarbonate solution. The layerswere separated and aqueous layer was extracted twice with ethyl acetate.The organic layers were combined, dried with magnesium sulfate and thenconcentrated under reduced pressure to provide a brown solid. Thismaterial was purified by chromatography (silica gel eluting with 60/40ethyl acetate/hexanes) to provide 55 g of2,4-dichloro-5,6-dimethyl-3-nitropyridine.

Part B

Tert-butyl 4-aminobutylcarbamate (60 g, 339 mmol) was slowly added to amixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (50 g, 226 mmol),anhydrous N,N-dimethylformamide (500 mL) and triethylamine (50 mL, 339mmol). The reaction mixture was allowed to stir overnight and then itwas concentrated under reduced pressure to provide an oil. The oil wasdissolved in ethyl acetate and then washed with water. The organic layerwas dried over magnesium sulfate and then concentrated under reducedpressure to provide a dark oil. This material was purified by columnchromatography (silica gel eluting with 40/60 ethyl acetate/hexanes) toprovide 64.5 g of tert-butyl4-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)butylcarbamate as a brightorange oil which solidified on standing.

Part C

A solution of phenol (18.50 g, 196 mmol) in diglyme (50 mL) was slowlyadded dropwise to a chilled (0° C.) suspension of sodium hydride (8.28 gof 60% in mineral oil, 207 mmol) in diglyme (50 mL). After 1 hr gasevolution ceased. A solution of tert-butyl4-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)butylcarbamate (68.95 g,185 mmol) in diglyme (200 mL) was slowly added dropwise to the reactionmixture. After the addition was complete the reaction mixture was heatedat reflux for 4 hrs. The reaction mixture was concentrated under reducedpressure to provide a black oil. The oil was dissolved in ethyl acetateand then extracted with 1N sodium hydroxide to remove excess phenol. Theorganic layer was dried over magnesium sulfate and then concentratedunder reduced pressure. The residue was purified by chromatography(silica gel eluting with 30/70 ethyl acetate/hexanes) to provide 40.67 gof tert-butyl4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butylcarbamate asan orange oil.

Part D

Tert-butyl4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butylcarbamate(9.17 g, 21.3 mmol), toluene (50 mL), isopropanol (5 mL) and 5% platinumon carbon (7.0 g) were combined and maintained under hydrogen pressure(50 psi, 3.5 Kg/cm²) overnight on a Parr apparatus. The catalyst wasremoved by filtration and the filtrate was concentrated under reducedpressure. The resulting brown oil was dried under high vacuum to provide7.47 g of tert-butyl4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate.

Part E

A mixture of the material from Part D, triethyl orthoacetate (3.59 mL,19.58 mmol), anhydrous toluene (75 mL) and pyridine hydrochloride (0.75g) was heated at reflux for 1 hour and then concentrated under reducedpressure to provide a brown oil. The oil was dissolved in ethyl acetateand then washed with water (×2), washed with brine, dried over magnesiumsulfate and then concentrated under reduced pressure to provide 6.74 gof tert-butyl4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamateas a brown oil.

Part F

A solution of tert-butyl4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamate(6.70 g, 15.8 mmol) in dichloromethane (50 mL) was slowly added to achilled (0° C.) mixture of trifluoroacetic acid (60 mL) anddichloromethane (100 mL). The reaction mixture was allowed to warm toambient temperature and then left overnight. The reaction mixture wasconcentrated under reduced pressure to provide a brown oil. The oil wasdissolved in dichloromethane and the solution was made basic (pH 14)with 5% aqueous sodium hydroxide. The layers were separated and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over magnesium sulfate and then concentrated underreduced pressure to provide 4.50 g of4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylamine asa brown oil.

Part G

A mixture of the material from Part F, triethylamine (2.0 mL, 14.6 mmol)and anhydrous acetonitrile (450 mL) was heated until a homogeneoussolution was obtained. Methanesulfonic anhydride (2.54 g, 14.6 mmol) wasslowly added to the reaction mixture. The reaction was judged to becomplete in 10 minutes. The reaction mixture was concentrated underreduced pressure to provide a brown oil. The oil was dissolved indichloromethane and was washed with 5% aqueous sodium hydroxide. Theaqueous layer was separated and then extracted with dichloromethane. Theorganic layers were combined, dried over magnesium sulfate and thenconcentrated under reduced pressure to provide a brown solid. Thismaterial was purified by column chromatography (silica gel eluting with95/5 dichloromethane/methanol) to provide 4.49 g ofN-[4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamideas a light brown solid.

Part H

N-[4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide(4.20 g, 10.4 mmol) and ammonium acetate (42 g) were combined and thenheated in a sealed tube at 150° C. for 36 hrs. The reaction mixture wasallowed to cool and then it was dissolved in chloroform. The solutionwas extracted with 10% aqueous sodium hydroxide solution. The aqueouslayer was separated and then extracted multiple times with chloroform.The organic layers were combined, dried over magnesium sulfate and thenconcentrated under reduced pressure to provide a yellow oil. The oil wasdissolved in methanol and combined with 1M hydrochloric acid in diethylether (10.4 mL). The resulting white precipitate was isolated byfiltration and dried. The solid was dissolved in water and the solutionwas adjusted to pH 10 with solid sodium carbonate. The resulting whiteprecipitate was isolated by filtration, washed with diethyl ether andthen dried in a vacuum oven at 80° C. to provide 2.00 g ofN-[4-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide,m.p. 228-230°C.

Analysis: Calculated for C₁₄H₂₃N₅O₂S: % C, 51.67; % H, 7.12; % N, 21.52;Found: % C, 51.48; % H, 6.95; % N, 21.51.

EXAMPLE 8N-{4-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamide

Part A

Triethylamine (3.3 mL, 23.7 mmol) was added to a chilled (0° C.) mixtureof tert-butyl4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate(8.60 g, 21.5 mmol) and anhydrous dichloromethane (200 mL). Ethoxyacetylchloride (2.76 g, 22.5 mmol) was added. After one hour the reactionmixture was allowed to warm to ambient temperature and stirred for 2hours. The reaction mixture was concentrated under reduced pressure toprovide tert-butyl4-({3-[(ethoxyacetyl)amino]-5,6-dimethyl-2-phenoxypyridin-4-yl}amino)butylcarbamateas a brown oil. The oil was combined with pyridine (130 mL) and heatedat reflux overnight. The reaction mixture was concentrated under reducedpressure to provide a brown oil. The oil was dissolved indichloromethane and was washed with water. The organic layer was driedover magnesium sulfate and then concentrated under reduced pressure. Theresidue was dissolved in diethyl ether and then concentrated underreduced pressure to provide 8.21 g of tert-butyl4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamate.

Part B

Using the method of Part F of Example 7, the material from Part A washydrolyzed to provide 5.76 g of4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butan-1-amineas a brown oil.

Part C

Using the method of Part G of Example 7,4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butan-1-amine(5.52 g, 15.0 mmol) was reacted with methanesulfonic anhydride (2.74 g,15.7 mmol) to provide 6.26 g ofN-{4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamideas a brown solid.

Part D

Using the general method of Part H of Example 7,N-{4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamide(5.86 g, 13.1 mmol) was aminated to provide 1.58 g ofN-{4-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamideas a white solid, m.p. 165-167° C.

Analysis: Calculated for C₁₆H₂₇N₅O₃S: % C, 52.01; % H, 7.37; % N, 18.95;Found: % C, 51.83; % H, 7.39; % N, 18.88.

EXAMPLE 9

N-[4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide

Part A

Under a nitrogen atmosphere,4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butan-1-amine(122 mg, 0.33 mmol) was dissolved in dichloromethane and triethylamine(0.093 mL, 0.67 mmol). The solution was cooled in an ice-water bath and4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzoyl chloride (106 mg,0.33 mmol) was dissolved/slurried in dichloromethane and added dropwise.The ice bath was removed and the reaction was stirred for an additional16 hours. The reaction was quenched with 10% aqueous sodium carbonate.The phases were separated and the aqueous fraction was extracted withdichloromethane. The organic fractions were combined, washed with waterfollowed by brine, dried (Na₂SO₄), decanted and evaporated to yield ayellow oil. Purification by flash column chromatography (silica gel,92:8 dichloromethane/methanol gradient to 95:5 dichloromethane/methanol)provided 101 mg ofN-[4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamideas a pale yellow solid. The product was determined to be 97+% pure byHPLC. MS(CI): 648 (M+H).

Part B

N-[4-(2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide(101 mg, 0.16 mmol) and ammonium acetate (1.1 g) were placed into apressure tube along with a stir bar. The tube was sealed and heated at150° C. for 16 hours. The reaction was cooled to room temperature anddiluted with water. The resulting cloudy aqueous mixture was made basicwith 10% aqueous sodium hydroxide and extracted with chloroform (3×25mL). The combined organic fractions were washed with water followed bybrine, dried (Na₂SO₄), decanted and evaporated to provide a yellow oil.Purification by flash column chromatography (silica gel, 95:5dichloromethane/methanol gradient to 9:1 dichloromethane/methanol andfinally 94:5:1 dichloromethane/methanol/triethylamine) provided 14 mg ofN-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamideas a yellow oil. ¹H-NMR (500 MHz, DMSO-d₆) δ 8.41 (t, J=5.5 Hz, 1H),7.76 (d, J=8.3 Hz, 2H); 7.43 (d, J=8.3, 2H), 7.37-7.31 (m, 4H),7.26-7.22 (m, 1H), 5.84 (bs, 2H), 5.52 (s, 1H), 4.22 (t, J=7.7 Hz, 2H),3.49 (t, J=5.8 Hz, 2H), 3.29 (dd, J=6.4, 12.4 Hz, 2H), 2.76 (t, J=7.7Hz, 2H), 2.58 (t, J=5.7 Hz, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.22 (s,6H), 1.73-1.65 (m, 4H), 1.61-1.55 (m, 2H), 1.35 (sextet, J=7.4 Hz, 2H),0.86 (t, J=7.4 Hz, 3H); ¹³C-NMR (125 MHz, DMSO-d₆) δ 165.9, 153.0,148.1, 145.4, 142.0, 138.6, 133.5, 128.23, 127.4, 127.3, 127.1, 126.4,126.1, 124.5, 103.0, 82.0, 66.3, 58.0, 45.2, 43.6, 38.4, 29.3, 28.8,26.1, 26.0, 21.7, 21.0, 13.6, 12.2. HRMS (CI) m/e 571.3763 (M+H),(571.3761 calcd for C₃₄H₄₇N₆O₂, M+H).

EXAMPLE 10

N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamide

Part A

A mixture of 6-methyl-3-nitropyridine-2,4-diol (50 g, 0.29 mol) andphosphorus oxychloride (500 mL) was heated at 90° C. overnight. Theexcess phosphorus oxychloride was removed under reduced pressure. Theresulting black oil was poured into water (1.8 L) and ice. This mixturewas extracted with chloroform (×8, 3 L total) and filtered to removeblack particulates and break up an emulsion. The combined organics werewashed with 10% sodium carbonate (×2) and brine, dried and thenconcentrated under reduced pressure to provide 52 g of an amber oil.This oil was recrystallized from heptane (115 mL) to provide 43.5 g of2,4-dichloro-6-methyl-3-nitropyridine as large amber crystals.

Part B

A solution of tert-butyl 4-aminobutylcarbamate (32.12 g, 170.6 mmol) inN,N-dimethylformamide (200 mL) was added over a period of 90 minutes toa solution of 2,4-dichloro-6-methyl-3-nitropyridine (35.09 g, 169.5mmol) in N,N-dimethylformamide (500 mL). The reaction mixture wasstirred at ambient temperature overnight. The solvent was removed byvacuum distillation using a 24/40 short path distillation head and warmwater. The residue was dissolved in ethyl acetate (700 mL), washed withwater (3×100 mL), dried over magnesium sulfate and then concentratedunder reduced pressure. The crude product was purified by columnchromatography (50×450 mm silica gel eluting with 1:1 hexane:ethylacetate) to provide 59.90 g of tert-butyl4-[(2-chloro-6-methyl-3-nitropyridin-4-yl)amino]butylcarbamate.

Part C

Phenol (9.45 g, 100 mmol) was added over a period of 10 minutes to achilled (0° C.) suspension of sodium hydride (4.24 g of 60%, 106 mmol)in anhydrous tetrahydrofuran (100 mL). The reaction mixture was allowedto stir at 0° C. for 30 minutes. A solution of tert-butyl4-[(2-chloro-6-methyl-3-nitropyridin-4-yl)amino]butylcarbamate (33.92 g,94.5 mmol) in anhydrous tetrahydrofuran (250 mL) was added over a periodof 50 minutes while maintaining the reaction mixture at 0° C. Thereaction mixture was allowed to warm to ambient temperature and stirredovernight before being concentrated under reduced pressure. The residuewas dissolved in ethyl acetate (500 mL), washed with 1N sodium hydroxide(300 mL), dried over magnesium sulfate and then concentrated to dryness.The crude product was purified by column chromatography (400 g silicagel eluting with 7:3 hexanes:ethyl acetate to provide 25.4 g oftert-butyl4-[(6-methyl-3-nitro-2-phenoxypyridin-4-yl)amino]butylcarbamate.

Part D

A solution of the material from Part C in a mixture of toluene (300 mL)and isopropanol (33 mL) was combined with catalyst (16.68 g of 5% Pt/C)and placed under hydrogen pressure (30 psi, 2.1 Kg/cm²; recharging once)on a Parr apparatus for 5 hours. The reaction mixture was filtered toremove the catalyst and then concentrated under reduced pressure toprovide 23.4 g of tert-butyl4-[(3-amino-6-methyl-2-phenoxypyridin-4-yl)amino]butylcarbamate as adark oil.

Part E

The material from Part D was dissolved in dichloromethane (500 mL) andthen cooled under a nitrogen atmosphere to 0° C. A solution ofethoxyacetyl chloride (7.9 g, 63.5 mmol) in dichloromethane (200 mL) wasadded over a period of 40 minutes while maintaining the reaction mixtureat 0° C. The reaction mixture was allowed to warm to ambient temperatureand was stirred overnight. The reaction mixture was washed with water(2×100 mL) and brine (100 mL), dried over magnesium sulfate and thenconcentrated under reduced pressure to provide 26.4 g of tert-butyl4-({3-[(ethoxyacetyl)amino]-6-methyl-2-phenoxypyridin-4-yl}amino)butylcarbamate.

Part F

The material from Part E was combined with pyridine (250 mL) andpyridine hydrochloride (20.85 g, 180 mmol) and heated at reflux under anitrogen atmosphere overnight. The bulk of the pyridine was removed byvacuum distillation. The residue was partitioned between ethyl acetate(600 mL) and water (300 mL). The layers were separated. The organiclayer was washed with water (2×300 mL), dried over magnesium sulfate andthen concentrated under reduced pressure to provide 8.17 g of tert-butyl4-[2-(ethoxymethyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamateas a dark oil. The pH of the aqueous layer was adjusted to 11 with 15%sodium hydroxide and then it was extracted with ethyl acetate (5×250mL). The extracts were combined, dried over magnesium sulfate and thenconcentrated under reduced pressure to provide 9.46 g of4-[2-(ethoxymethyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butan-1-amine.

Part G

Methane sulfonic anhydride (0.822 g, 4.72 mmol) was added over a periodof 5 minutes to a solution of4-[2-(ethoxymethyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butan-1-amine(1.5 g, 4.23 mmol) in a mixture of chloroform (35 mL) and triethylamine(0.77 mL). The reaction mixture was allowed to stir for 2.5 hours thenit was washed with 1 N sodium hydroxide (10 mL), dried over magnesiumsulfate and then concentrated under reduced pressure to provide 2.6 g ofcrudeN-[4-(2-ethoxymethyl-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide.

Part H

The crude material from Part G was combined with ammonium acetate (25.37g) and heated at 150° C. in a pressure vessel for 14.5 hours. Thereaction mixture was allowed to cool to ambient temperature then it waspartitioned between chloroform (250 mL) and 10% sodium hydroxide. Theaqueous layer was extracted with chloroform (5×100 mL). The combinedorganics were dried over magnesium sulfate and then concentrated underreduced pressure to provide a brown oil. The oil was purified by columnchromatography (10 g of silica gel eluting with 2% methanol inchloroform containing 0.5% triethylamine) to provide 0.514 g of product.This material was dissolved in hot chloroform, treated with activatedcarbon, then filtered and concentrated under reduced pressure to provide0.37 g ofN-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamideas a solid, m.p. 162-164° C.

Analysis: Calculated for C₁₅H₂₅N₅O₃S0.05 HCl: % C, 50.43; % H, 7.07; %Cl, 0.50; % N 19.60; Found: % C, 50.36; % H, 6.94; % Cl, 0.63; % N,19.54. ¹H NMR (300 MHz, CDCl₃) δ 6.53 (s, 1 H), 5.09 (s, 2 H), 4.71 (s,2 H), 4.55 (bs, 1 H), 4.16 (t, J=7.5 Hz, 2 H), 3.58 (quartet, J=7.1 Hz,2 H), 3.16 (m, 2 H), 2.93 (s, 3 H, 2.47 (s, 3 H),1.92 (quintet, J=7.5Hz, 2 H), 1.64 (quintet, J=7.2 Hz, 2H), 1.23 (t, J=6.9 Hz, 3 H); MS(CI)m/e 356 (M+H)

EXAMPLE 112-(ethoxymethyl)-6,7-dimethyl-1-{2-[1-(methylsulfonyl)piperidin-4-yl]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine

Part A

A solution of 4-(2-aminoethyl)-1-benzylpiperidine (9.88 g, 45.2 mmol) inN,N-dimethylformamide was added dropwise to a solution of2,4-dichloro-5,6-dimethyl-3-nitropyridine (10.00 g, 45.2 mmol) andtriethylamine (12.6 mL, 90.5 mmol) in N,N-dimethylformamide (320 mL).The reaction mixture was allowed to stir at ambient temperature forabout 20 hours and then it was concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and water. The layers wereseparated and the aqueous layer was extracted with ethyl acetate. Theorganics were combined, washed with brine, dried over sodium sulfate andthen concentrated under reduced pressure to provide an orange oil. Theoil was purified by flash chromatography (400 mL silica gel elutinginitially with 10% ethyl acetate in hexane, then with 15% ethyl acetatein hexane and finally with 40% ethyl acetate in hexane) to provide 11.00g ofN-[2-(1-benzylpiperidin-4-yl)ethyl]-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine.

Part B

Sodium hydride (1.196 g of 60%, 29.9 mmol) was added to a solution ofphenol (2.81 g, 29.9 mol) in diglyme (40 mL). The mixture was stirredfor 15 minutes after the cessation of gas evolution. A solution ofN-[2-(1-benzylpiperidin-4-yl)ethyl]-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine(10.9 g, 27.2 mmol) in hot diglyme was added to the phenoxide mixture.The reaction mixture was heated at reflux for 1.5 hours, cooled toambient temperature, and then concentrated to remove the diglyme (60° C.bath, 21 Pa). The residue was purified by column chromatography elutingfirst with 1% methanol in dichloromethane to elute residual diglyme andthen with 5% methanol in dichloromethane to remove product. Thefractions were concentrated to provide 5.91 g ofN-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amineas an orange-brown oil which solidified on standing.

Part C

Sodium borohydride (0.727 g, 19.2 mmol) was added in portions over aperiod of 20 minutes to a solution of nickel(II)chloride hexahydrate(1.52 g, 6.40 mmol) in methanol. A solution of the material from Part Bin methanol was added dropwise over a period of 15 minutes. More sodiumborohydride (50 mg) was added. The reaction mixture was filtered througha layer of filter agent and the filter was washed with methanol. Thefiltrate was concentrated under reduced pressure. The residue waspurified by chromatography (plug of silica gel eluting with 2% methanolin dichloromethane) to provide 4.6 g ofN⁴-[2-(1-benzylpiperidin-4-yl)ethyl]-5,6-dimethyl-2-phenoxypyridine-3,4-diamineas an orange-brown oil which solidified on standing.

Part D

Ethoxyacetyl chloride (1.31 g, 10.7 mmol) was added dropwise to asolution of the material from Part C and triethylamine (1.64 mL, 13mmol) in dichloromethane (60 mL). The reaction was stirred for about 20hours and then concentrated under reduced pressure to provide crudeN-(4-{[2-(1-benzylpiperidin-4-yl)ethyl]amino}-5,6-dimethyl-2-phenoxypyridin-3-yl)-2-ethoxyacetamide.The acetamide was dissolved in pyridine (60 mL), pyridine hydrochloride(1.17 g) was added and the reaction mixture was heated at reflux for 4hours. The reaction mixture was allowed to cool to ambient temperatureand then the pyridine was removed under reduced pressure. The residuewas diluted with 5% sodium carbonate (100 mL) and water (50 mL) thenpartitioned into dichloromethane (300 mL). The organic layer was washedwith water and brine, dried over magnesium sulfate and then concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with 2% methanol in dichloromethane to provide5.1 g of1-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridineas an orange-red solid.

Part E

The material from Part D and ammonium acetate (51 g) were combined in apressure flask (350 mL). The flask was sealed and then heated at 150° C.for 24 hours followed by heating at 170° C. overnight. The reactionmixture was cooled and then poured into water. The resulting solutionwas made basic with ammonium hydroxide and then extracted withchloroform (×2). The combined organics were washed with brine, driedover magnesium sulfate and then concentrated under reduced pressure. Theresidue was dissolved in isopropanol (50 mL). Ethanesulfonic acid (21mmol) was added dropwise and the mixture was heated at reflux for 30minutes. The reaction was allowed to cool to ambient temperatureovernight and then it was concentrated under reduced pressure. Theresulting oily residue was dissolved in water (200 mL), extracted withdichloromethane (×3) and then made basic (pH 14) with 10% sodiumhydroxide. The aqueous layer was extracted with chloroform (×3). Thecombined organics were washed with brine, dried over magnesium sulfateand then concentrated to provide a brown oil which solidified. The solidwas recrystallized from acetonitrile to provide 2.54 g of a tan solid.The solid was dissolved in 2% methanol in dichloromethane and loadedonto a silica gel (130 g) column. The column was eluted with 2% methanolin dichloromethane with 1% triethylamine. The fractions wereconcentrated to provide 2.4 g of1-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amineas an off-white solid.

Part F

The material from Part E was dissolved in a boiling mixture of 50/50ethanol/methanol. The solution was allowed to cool slightly and then itwas added to a Parr flask containing palladium on carbon (0.60 g) thathad been wetted with ethanol. The flask was placed under hydrogenpressure for about 40 hours during which time an additional 1.7 g ofcatalyst was added. The reaction mixture was filtered through a layer offilter agent and the filter cake was washed with methanol. The filtratewas concentrated under reduced pressure. The residue was combined withdichloromethane and then concentrated. The resulting solid was driedunder high vacuum to provide 1.5 g of2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine.

Part G

Methane sulfonic anhydride (0.161 g, 0.923 mmol) was added in a singleportion to a chilled (0° C.) slurry of2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine(0.306 g, 0.923 mmol) in dichloromethane (10 mL). The reaction wasallowed to stir overnight then more methane sulfonic anhydride (20 mg)was added. The reaction mixture was diluted with chloroform and thenpoured into 5% sodium hydroxide (25 mL). The organic layer was washedwith water and brine, dried over magnesium sulfate and then concentratedunder reduced pressure to a white solid. This material was combined withdichloromethane and hexane (4 mL) and then concentrated under reducedpressure to provide a white solid. This material was recrystallized fromacetonitrile to provide 237 mg of2-(ethoxymethyl)-6,7-dimethyl-1-{[2-1-(methanesulfonyl)piperidin-4-yl]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, m.p. 214.7° C.

Analysis: Calculated for C₁₉H₃₁N₅O₃S: % C, 55.72; % H, 7.63; % N, 17.10;Found: % C, 56.08; % H, 7.45; % N, 17.32. ¹H NMR (300 MHz, DMSO-d₆) δ5.76 (s, 2 H), 4.64 (s, 2 H), 4.35-4.29 (m, 2 H), 3.6-3.48 (m, 4 H),2.85 (s, 3 H), 2.71 (dt, J=10, 2.1 Hz, 2 H), 2.39 (s, 3 H), 2.31 (s, 3H), 1.83 (d, j=10.8 Hz, 2 H), 1.75-1.67 (m, 2 H), 1.62-1.48 (m, 1H),1.34-1.20 (m, 2H), 1.15 (t, J=7.0 Hz, 3 H); ¹³C NMR (75 Hz, DMSO-d₆) δ149.3, 148.3, 146.4, 138.8, 124.5, 102.7, 65.2, 64.5, 45.4, 42.6, 37.7,34.0, 32.7, 30.9, 21.9, 14.9, 12.4; MS(CI) m/e 410.2209 (410.2226 calcdfor C₁₉H₃₁N₅O₃S, M+H).

EXAMPLE 12N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]methanesulfonamide

Part A

A solution of tert-butyl 3-aminopropylcarbamate (121.39 g, 697 mmol) inN,N-dimethylformamide (200 mL) was slowly added to a solution of2,4-dichloro-5,6-dimethyl-3-nitropyridine (110 g, 498 mmol) andtriethylamine (104 mL, 746 mmol) in N,N-dimethylformamide (900 mL).After stirring at ambient temperature for 20 hours the reaction mixturewas heated to 55° C. At 24 hours 0.1 equivalents of the carbamate wasadded. The reaction mixture was allowed to cool to ambient temperatureovernight and then concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (3 L). The solution was divided into 3aliquots (1 L each). Each aliquot was washed with water (2×1 L). The pHof the aqueous washes was adjusted to 10 with potassium carbonate andthen they were extracted with ethyl acetate. All of the ethyl acetatelayers were combined, dried over sodium sulfate and then concentratedunder reduced pressure to provide 181 g of crude product. This materialwas recrystallized from acetonitrile to provide 138 g of tert-butyl3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propylcarbamate as ayellow solid.

Part B

Sodium hydride (17.23 g of 60%) was washed with hexanes to remove themineral oil and then combined with diglyme (50 mL). Under a nitrogenatmosphere the mixture was cooled. A solution of phenol (35.82 g, 408mmol) in diglyme (150 mL) was added dropwise. The reaction mixture wasstirred for 15 minutes after the cessation of gas evolution. Thematerial from Part A was added. The reaction mixture was heated at 62°C. for several days, then the temperature was increased to 120° C. andthe reaction was stirred overnight. The reaction mixture was allowed tocool to ambient temperature, then it was combined with water (4 L),stirred for about 4.5 hours and then allowed to stand overnight. Thesolids were dissolved in ethyl acetate and then filtered to removeparticulates. The filtrate was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (˜2 L), washed with saturatedpotassium carbonate (3×2 L), dried over magnesium sulfate and thenconcentrated under reduced pressure to provide 152.3 g of tert-butyl3-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]propylcarbamate.

Part C

A mixture of 5% Pt/C (85 g) and toluene (50 mL) was added to a solutionof the material from Part B in a mixture of toluene (1850 mL) andisopropanol (125 mL) in a hydrogenation flask. The flask was placedunder a hydrogen atmosphere overnight. Another 22.5 g of catalyst wasadded and the flask was placed back on the hydrogenator. After 6 hourscatalyst (40 g) and isopropanol (50 mL) were added. The flask was placedback on the hydrogenator overnight. The reaction mixture was filtered toremove the catalyst. The filtrate was concentrated under reducedpressure to provide tert-butyl3-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]propylcarbamate asan oil. The oil was dissolved in pyridine (1300 mL).

Part D

A portion (650 mL) of the pyridine solution from Part C was cooled in anice bath for 10 minutes. Acetyl chloride (12.65 mmol, 0.1779 mmol) wasslowly added over a period of 5 minutes. The reaction mixture wasremoved from the ice bath and heated to reflux. The temperature wasreduced to 110° C. and the reaction mixture was stirred overnight. Thepyridine was removed under reduced pressure. The residue was slurriedwith heptane and then concentrated under reduced pressure. The residuewas combined with ethyl acetate (1 L) and water (1 L). The pH wasadjusted to 12 with 50% sodium hydroxide and the layers were separated.The organic layer was filtered to remove particulates and thenconcentrated under reduced pressure. The residue was purified by ethylacetate slurry to provide 39.8 g of tert-butyl3-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine-1-yl)propylcarbamateas a light brown fluffy solid.

Part E

The material from Part D was combined with ammonium acetate (410 g) in a2 L flask. A wad of paper towels was stuffed into the neck of the flask.The reaction mixture was heated with stirring at 145° C. for 20.5 hours.The reaction mixture was allowed to cool to ambient temperature, the pHwas adjusted to 11 with ammonium hydroxide and the mixture was extractedwith chloroform. The extract was washed with 1% sodium carbonate (7×1L). The original aqueous phase and the first three washes were combined,filtered to remove particulates and then concentrated to a volume ofabout 1 L. This solution was run overnight on a continuous extractionapparatus with chloroform. The chloroform extract was concentrated underreduced pressure to provide 27.1 g of an off-white solid. This materialwas slurried with methyl acetate to provide about 16.5 g ofN-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]acetamide.A portion (0.5 g) was recrystallized from acetonitrile to provide about0.3 g of the pure acetamide as a white solid, m.p. 181.4-182.1° C.Analysis: Calculated for C₁₄H₂₁N₅O. 0.50 H₂O: % C, 59.13; % H, 7.80; %N, 24.63; Found: % C, 59.08; % H, 8.00; % N, 24.73.

Part F

Concentrated hydrochloric acid (5 mL) was slowly added to a solution ofN-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]acetamide(15.94 g, 57.9 mmol) in absolute ethanol (100 mL). A precipitate formedimmediately and the mixture thickened. Ethanol (50 mL) was addedfollowed by the addition of concentrated hydrochloric acid (119.5 mL).The reaction mixture was heated at reflux for 2 days. The solvents wereremoved under reduced pressure. Water (250 mL) was added to the residue,solid potassium carbonate was added until the pH reached 7 at which timechloroform (250 mL) was added. Sodium carbonate addition was resumeduntil the pH reached 10, then 50% sodium hydroxide was added until thepH reached 14. The mixture was diluted with additional chloroform (500mL) and then stirred at ambient temperature for 2 days. The organiclayer was separated, dried with magnesium sulfate and then concentratedunder reduced pressure. The residue was recrystallized from acetonitrileto provide 8.42 g of1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine as anoff-white crystalline solid, m.p. 191.5-191.9° C. Analysis: Calculatedfor C₁₂H₁₉N₅.0.25 H₂O: % C, 60.61; % H, 8.26; % N, 29.45; Found: % C,60.50; % H, 8.28; % N, 29.57.

Part G

Methanesulfonyl chloride (0.86 mL, 11.1 mmol) was added to a chilled(0°) solution of1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00g, 4.3 mmol) in a mixture of chloroform (50 mL) and triethylamine (1.85mL, 13.3 mmol). After 15 minutes the reaction mixture was removed fromthe ice bath and allowed to stir at ambient temperature overnight. Threeportions of triethylamine (0.6 eq) and methane sulfonyl chloride (0.5eq) were added over a period of about 5 hours then the reaction wasallowed to stir overnight. The reaction mixture was diluted with waterand then extracted with chloroform in a continuous extraction apparatusover the weekend. The chloroform extract was concentrated under reducedpressure to provide a yellow oil. The oil was purified by columnchromatography eluting with 0-5% methanol gradient in chloroform toprovide 0.61 g of a solid. This material was recrystallized from amixture of acetonitrile, isopropanol and water to provide 0.31 g of themethane sulfonic acid salt ofN-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]methanesulfonamideas colorless crystals, m.p. 241.6-242.2° C.

Analysis: Calculated for C₁₃H₂₁N₅O₂S.CH₄O₃S: % C, 41.26; % H, 6.18; % N,17.19; Found: % C, 41.36; % H, 6.35; % N, 17.32. ¹H NMR (Bruker 300 MHz,DMSO-d₆) δ 12.76 (s, 1 H), 7.81 (s, 2 H), 7.18 (t, J=5.6 Hz, 1 H), 4.36(t, J=8.1, 2 H), 3.09 (q, J=6.2 Hz, 2 H), 2.93 (s, 3 H), 2.58 (s, 3 H),2.42 (s, 6 H), 2.36 (s, 3 H), 1.90 (p, J=8.1 Hz, 2 H). MS(CI) m/e 408(M+H).

EXAMPLE 13N-{3-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]propyl}methanesulfonamide

Part A

Using the general method of Example 12 Part D, a pyridine solution oftert-butyl3-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]propylcarbamate(see Example 12 Part C) was treated with ethoxyacetyl chloride (21.81 g,178 mmol). The crude product was combined with dichloromethane (2 L) andwater (2 L). The pH was adjusted to 12 with 50% sodium hydroxide and themixture was stirred for 30 minutes. The organic phase was separated,dried over magnesium sulfate and then concentrated under reducedpressure. The residue was diluted with heptane and then concentrated toremove residual pyridine. This procedure was repeated several times toprovide 64.8 g of tert-butyl3-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]propylcarbamateas a brown tar.

Part B

Ammonium acetate (500 g) and tert-butyl3-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]propylcarbamate(35.09 g, 77 mmol) were combined in a 2 L flask. The neck of the flaskwas stuffed with a wad of paper towels. The reaction mixture was heatedwith stirring at 150° C. for 27 hours. The reaction mixture was allowedto cool to ambient temperature and then it was placed in an ice bath.Ammonium hydroxide was added until the pH reached 11. Sodium hydroxide(50%) was added until the pH reached 14. The resulting precipitate wasisolated by filtration and then dissolved in chloroform (4 L). Thechloroform solution was divided into two portions and each was washedwith saturated potassium carbonate (2×2 L). The organics were combined,dried over magnesium sulfate and then concentrated under reducedpressure to provide 30.3 g of crude product. This material was slurriedwith methyl acetate to provide 13.7 g ofN-{3-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]propyl}acetamideas a gray solid, m.p. 161.8-162.3° C.

Analysis: Calculated for C₁₆H₂₅N₅O₂: % C, 60.17; % H, 7.89; % N, 21.93;Found: % C, 59.97; % H, 7.70; % N, 22.19. ¹H NMR (Bruker 300 MHz,CHCl₃-d) δ 4.91 (s, 2 H), 4.73 (s, 2 H), 4.43 (t, J=8.1 Hz, 2 H), 3.59(q, J=6.8 Hz, 2 H), 2.81 (t, J=6.8 Hz, 2 H), 2.47 (s, 3 H), 2.45 (s, 3H), 1.94 (p, J=8.1 Hz, 2 H), 1.22 (t, J=6.8 Hz, 3 H), 1.08 (s, 2 H).MS(CI) m/e 278 (M+H).

Part C

Using the general method of Example 12 Part F,N-{3-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]propyl}acetamide(13.14 g, 4.1 mmol) was hydrolyzed and purified to provide 10.81 g of1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a brown solid, m.p. 126.8-127.2° C.

Analysis: Calculated for C₁₄H₂₃N₅O: % C, 60.62; % H, 8.36; % N, 25.25;Found: % C, 60.49; % H, 8.38; % N, 25.33.

Part D

Using the general method of Example 12 Part G,1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine(1.00 g, 3.6 mmol) was reacted with methanesulfonyl chloride to provide0.67 g ofN-{3-[4-amino-2-(ethoxymethyl)-6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl]propyl}methanesulfonamideas an off white solid, m.p. 223.2-223.9° C.

Analysis: Calculated for C₁₅H₂₅N₅O₃S: % C, 50.69; % H, 7.09; % N, 19.70;Found: % C, 50.44; % H, 6.95; % N, 19.67. H NMR (Bruker 300 MHz,DMSO-d₆) δ 7.18 (t, J=5.6 Hz, 1 H), 5.74 (s, 2 H), 4.64 (s, 2 H), 4.33(t, J=8.1 Hz, 2 H), 3.53 (q, J=7.5 Hz, 2 H), 3.06 (q, J=6.2 Hz, 2 H),2.91 (s, 3 H), 2.39 (s, 3 H), 2.31 (s, 3 H), 1.92 (p, J=8.1 Hz, 2 H),1.14 (t, J=6.8 Hz, 3 H). MS(CI) m/e 356 (M+H).

EXAMPLE 14N-{4-[4-amino-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamide

Part A

Propanenitrile (120 mL) was added to malonyl dichloride (100 g) and thereaction mixture was stirred under nitrogen for 24 hours. Dioxane (200mL) was added. The resulting solid was isolated by filtration, washedwith water and suction dried. It was dissolved in methanol (˜75 mL) andthen combined with dioxane (300 mL). The reaction volume was reducedunder reduced pressure until a thick precipitate formed. The resultingprecipitate was isolated by filtration, washed with dioxane, and airdried to provide 64.4 g of 6-chloro-4-hydroxy-5-methyl-1H-pyridin-2-onehydrochloride as a white solid.

Part B

6-Chloro-4-hydroxy-5-methyl-1H-pyridin-2-one hydrochloride (64 g) wasdissolved in sulfuric acid (325 mL) while cooling in an ice bath. Nitricacid was added drop wise over a period of 90 minutes. The reactionmixture was allowed to stir for an additional 30 minutes and then it waspoured into ice water (2 L). The resulting precipitate was isolated byfiltration, washed with water and then dried to provide 42.5 g of6-chloro-4-hydroxy-5-methyl-3-nitro-1H-pyridin-2-one as a light yellowsolid.

Part C

Triethylamine (102 mL, 742 mmol) was added to a cooled (ice bath)mixture of 6-chloro-4-hydroxy-5-methyl-3-nitro-1H-pyridin-2-one (50.6 g,247 mmol) and anhydrous dichloromethane (1800 mL).Trifluoromethanesulfonic anhydride (83.2 mL, 495 mmol) was addeddropwise over a period of 45 minutes. After 1 hour, tert-butyl4-aminobutylcarbamate (51.2 g, 272 mmol) was added over period of 20minutes. The reaction was allowed to warm to ambient temperatureovernight. The reaction mixture was washed with water (4×1 L), driedover magnesium sulfate, and then concentrated under reduced pressure toprovide an orange oil. The oil was purified by chromatography (1100 mLof silica gel eluting with 50/50 ethyl acetate/hexanes to provide 93.5 g4-({4-[(tert-butoxycarbonyl)amino]butyl}amino)-6-chloro-5-methyl-3-nitropyridin-2-yltrifluoromethanesulfonate as a yellow oil.

Part D

The crude product from Part C was combined with toluene (2 L),triethylamine (25.4 mL), and dibenzylamine (35.5 mL) and heated atreflux for 1 hour. The reaction mixture was allowed to cool to ambienttemperature, washed with water (4×1 L) and brine (200 mL), dried overmagnesium sulfate and then concentrated under reduced pressure toprovide 100 g of an orange oil. A portion (70 g) was purified by columnchromatography (1200 mL of silica gel eluting with 20/80 ethylacetate/hexanes) to provide 52 g of tert-butyl4-{[2-chloro-6-(dibenzylamino)-3-methyl-5-nitropyridin-4-yl]amino}butylcarbamateas a light yellow oil.

Part E

Sodium borohydride (0.40 g, 10.6 mmol) was slowly added to a solution ofnickel(II) chloride hexahydrate (0.70 g, 2.93 mmol) in methanol (75 mL).After 15 minutes a solution of tert-butyl4-{[2-chloro-6-(dibenzylamino)-3-methyl-5-nitropyridin-4-yl]amino}butylcarbamate(3.25 g, 5.87 mmol) dissolved in a mixture of methanol (25 mL) anddichloromethane (20 mL) was added to the reaction mixture. Sodiumborohydride (0.93 g) was slowly added. After 30 minutes analysis by highperformance liquid chromatography indicated that the reaction wascomplete. The reaction was scaled up to 48.7 g of the starting materialusing the same conditions. The small and large scale reaction mixtureswere combined and filtered through a layer of Celite® filter aid. Thefiltrate was passed through a plug of silica gel and the plug was washedwith 50/50 dichloromethane/methanol. The filtrate was concentrated underreduced pressure to provide 46.3 g of tert-butyl4-{[3-amino-6-chloro-4-(dibenzylamino)-5-methylpyridin-4-yl]amino}butylcarbamateas a light brown oil.

Part F

Triethylamine (12.2 mL) was added to a chilled (0° C.) solution of thematerial from Part E in dichloromethane (300 mL). A solution ofethoxyacetyl chloride (10.8 g) in dichloromethane (100 mL) was added viaan addition funnel. The reaction was allowed to warm to ambienttemperature overnight. Analysis indicated that some starting materialremained so 0.2 eq of the acid chloride was added. After 1 hour thereaction mixture was washed with water (3×500 mL), dried over magnesiumsulfate and then concentrated under reduced pressure to providetert-butyl4-{[2-chloro-6-(dibenzylamino)-5-(2-ethxoyacetylamino)-3-methylpyridin-4-yl]amino}butylcarbamateas a brown oil. The oil was dissolved in pyridine (300 mL). Pyridinehydrochloride (40 g) was added and the reaction mixture was heated atreflux for 4 hours. The reaction mixture was allowed to cool to ambienttemperature and then it was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (500 mL) and washed with water(500 mL). An emulsion formed and was cleared by adding sodium chlorideto the aqueous layer. The organic layer was dried over magnesium sulfateand concentrated under reduced pressure to provide 52.1 g of a darkbrown oil. This oil was purified by chromatography (silica gel elutingwith 30/70 ethyl acetate/hexanes) to provide 24.8 g of tert-butyl4-[6-chloro-4-(dibenzylamino)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamateas a light yellow oil.

Part G

Trifluoroacetic acid (160 mL) was added over a period of 15 minutes to achilled (0°) solution of the material from Part F in dichloromethane(500 mL). The reaction mixture was allowed to stir overnight and then itwas concentrated under reduced pressure. The residue was partitionedbetween dichloromethane (500 mL) and 10% sodium hydroxide (500 mL). Thebase layer was extracted with dichloromethane (×2). The combinedorganics were dried over magnesium sulfate and then concentrated underreduced pressure to provide a brown oil. The oil was dissolved inisopropanol (100 mL) and then combined with 41 mL of 1 M hydrochloricacid in diethyl ether. Diethyl ether (200 mL) was slowly added to themixture. The resulting precipitate was isolated by filtration, washedwith ether and dried in a vacuum oven at 80° C. overnight to provide11.25 g of the hydrochloride salt of the desired product as a whitesolid. The solid was dissolved in water (200 mL), combined with sodiumcarbonate (15 g), and then extracted with dichloromethane (3×500 mL).The combined extracts were dried over magnesium sulfate and thenconcentrated under reduced pressure to provide 10.2 g of1-(4-aminobutyl)-N,N-dibenzyl-6-chloro-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amineas a clear oil.

Part H

Under a nitrogen atmosphere, ammonium formate (13.7 g) was added to amixture of 10% palladium on carbon (10 g) and ethanol (200 mL). Thematerial from Part H was dissolved in a mixture of hot ethanol (600 mL)and methanol (400 mL) and then added to the reaction mixture. Thereaction mixture was heated at reflux for 4 hours and then allowed tocool to ambient temperature overnight. Analysis indicated that thereaction was only about one half complete so catalyst (5 g) and ammoniumformate (5 g) were added and the reaction mixture was heated at refluxfor 4 hours. The reaction mixture was allowed to cool to ambienttemperature and then it was filtered through a layer of Celite® filteraid. The filter cake was washed with 50/50 ethanol/methanol (1 L). Thesolvents were removed under reduced pressure to provide a clear oil. Theoil was partitioned between dichloromethane (500 mL) and 10% sodiumhydroxide (200 mL). The aqueous layer was extracted withdichloromethane. The combined organic layers were dried over magnesiumsulfate and then concentrated under reduced pressure to provide 4.30 gof1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amineas a clear oil which partially solidified on standing.

Part I

Methanesulfonyl chloride (4 eq) was added dropwise to a mixture of1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine(2.25 g, 8.11 mmol), triethylamine (10.2 mL, 73.0 mmol) and chloroform(225 mL). The solvent was removed under reduced pressure to provide anoil. The oil was dissolved in 10% sodium hydroxide (200 mL) thenextracted with chloroform (3×300 mL). The combined extracts were driedover magnesium sulfate and then concentrated under reduced pressure toprovide a clear oil. The oil was purified by column chromatography(silica gel eluting with 90/10 dichloromethane/methanol) to provide awhite solid. This material was dried overnight under vacuum at 80° C. toprovide 0.71 g ofN-{4-[4-amino-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamideas a white solid, m.p. 173-175° C.

Analysis: Calculated for C₁₅H₂₅N₅O₃S: % C, 50.69; % H, 7.09; % N, 19.70;Found: % C, 50.51; % H, 6.91; % N, 19.49.

EXAMPLES 15-30

Part A

A suspension of 5,6-dimethyl-3-nitropyridine-2,4-diol (14.87 g) inphosphorous oxychloride (150 mL) was heated at reflux for 2 hours.Excess phosphorous oxychloride was removed by distillation. The residuewas dissolved in water, neutralized with ammonium hydroxide, andextracted twice with ethyl acetate. The organics were combined, washedwith brine, dried over sodium sulfate and then concentrated underreduced pressure. The residue was slurried with boiling hexane and thenfiltered while hot. The filtrate was chilled. The resulting precipitatewas isolated by filtration and air dried to provide 6.8 g of2,4-dichloro-5,6-dimethyl-3-nitropyridine as a white powder.

Part B

A solution of tert-butyl 4-aminobutylcarbamate (8.52 g, 45.24 mmol) inN,N-dimethylformamide was added to a solution of2,4-dichloro-5,6-dimethyl-3-nitropyridine (10.00 g, 45.24 mmol) andtriethylamine (12.6 mL, 90.5 mmol) in N,N-dimethylformamide (320 mL).The reaction mixture was stirred overnight and then concentrated underreduced pressure. The residue was partitioned between water and ethylacetate. The layers were separated and the aqueous layer was extractedwith ethyl acetate. The organics were combined, washed with brine andthen concentrated under reduced pressure to provide a brown oilyresidue. This material was purified by flash chromatography (400 mLsilica gel, eluting initially with 10% ethyl acetate in hexane and thenincreasing the gradient to 15% and then to 25%) to provide 8.1 g oftert-butyl4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butylcarbamate as ayellow solid.

Part C

Phenol (2.164 g, 23.00 mmol) was added as a solid over a period of 10minutes to a suspension of sodium hydride (0.972 g, 24.3 mmol) indiglyme (24 mL). The reaction mixture was allowed to stir for 30 minutesthen the material from Part B was added as a solid. The reaction mixturewas stirred at 80° C. for 2.5 days and then allowed to cool to ambienttemperature overnight. The diglyme was removed under reduced pressure toprovide an oily residue. The residue was combined with cold water andallowed to stir overnight. Ethyl acetate was added and the layers wereseparated. The aqueous layer was extracted with ethyl acetate. Theorganics were combined, washed with water and brine, dried over sodiumsulfate and then concentrated under reduced pressure to provide a blackoil. This material was purified by flash chromatography (400 mL silicagel eluting with 25% ethyl acetate in hexanes) to provide 7.1 g oftert-butyl4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amine]butylcarbamate asan orange oil which later solidified.

Part D

A solution of tert-butyl4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butylcarbamate(7.32 g, 17.00 mmol) in a mixture of toluene (150 mL) and isopropanol(10 mL) was combined with a slurry of 10% palladium on carbon intoluene. The mixture was place under hydrogen pressure on a Parrapparatus for 24 hours. Additional catalyst was added at 1.5 hours (2.2g) and 3 hours (3 g). The reaction mixture was filtered through a layerof Celite® filter agent to remove the catalyst. The layer of filteragent was washed with ethanol (1 L), ethanol/methanol (1 L), andmethanol (1 L). The filtrate was concentrated under reduced pressure.The residue was combined with dichloromethane and heptane and thenconcentrated under reduced pressure to provide 6.17 g of tert-butyl4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate as asludgy brown yellow oil.

Part E

Diethoxymethyl acetate (2.76 mL, 16.93 mmol) and pyridine hydrochloride(0.037 g, 0.323 mmol) were added to a solution of the material from PartD in toluene (72 mL). The reaction mixture was heated at reflux for 2hours and then allowed to cool to ambient temperature overnight. Thereaction mixture was concentrated under reduced pressure and then theresidue was twice combined with toluene and concentrated. The resultingoil was dissolved in chloroform; washed with saturated sodiumbicarbonate, water and brine; dried over magnesium sulfate and thenconcentrated under reduced pressure to provide 5.37 g of tert-butyl4-(6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamateas a very thick brown oil/solid.

Part F

The material from Part E was combined with ammonium acetate (47 g) in atube. The tube was sealed and heated at 150° C. for 20 hours. Thereaction mixture was poured into water and adjusted to pH 10 with 10%sodium hydroxide. The basic solution was extracted with chloroform (×9).The basic layer was treated with solid sodium chloride and thenextracted with chloroform. The organics were combined, dried over sodiumsulfate and then concentrated under reduced pressure to provide ayellowish solid. The solid was dissolved in a mixture of chloroform andmethanol and then combined with 50 mL of 1N hydrochloric acid in diethylether. The solvents were removed and the resulting oil was dissolved inwater. This solution was extracted with dichloromethane (×3), made basic(pH 10) with 50% sodium hydroxide, and then extracted with chloroform(×3). Sodium chloride was added to the aqueous solution and it wasextracted with chloroform (×3). The organics were combined, dried oversodium sulfate and concentrated under reduced pressure to provide ayellow solid. This solid was recrystallized from ethanol to provide 2.62g of a solid. A portion (500 mg) was dissolved in methanol, concentratedunder reduced pressure and then dried in a vacuum oven at 70° C. overthe weekend to provide 0.46 g ofN-[4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]acetamideas a solid, m.p. 217-219° C.

Analysis: Calculated for C₁₄H₂₁N₅O: % C, 61.07; % H, 7.69; % N, 25.43;Found: % C, 60.87; % H, 7.75; % N, 25.43.

Part G

A solution ofN-[4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]acetamide(˜2.1 g) in 6 N hydrochloric acid (30 mL) was sealed in a flask and thenheated at 100° C. for about 30 hours. The reaction mixture was allowedto cool to ambient temperature and then filtered to remove anyparticulates. The filtrate was made basic (pH 14) with 25% sodiumhydroxide and then extracted with chloroform (×2). The aqueous layer wascombined with sodium chloride (20 g) and then extracted with chloroform(×3). The organics were combined, washed with brine, dried over sodiumsulfate and then concentrated under reduced pressure to provide 1.44 gof 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine.

Part H

The compounds in the table below were prepared using the followingmethod. The appropriate sulfonyl chloride (1.1 eq.) was added to a testtube containing a solution of1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (25 mg)in chloroform (5 mL). The test tube was capped and then placed on ashaker at ambient temperature overnight. The solvent was removed byvacuum centrifugation. The residue was purified by prep HPLC using themethod described above to provide the trifluoroacetate salt of thedesired compound. The table below shows the structure of the free baseand the observed accurate mass (m+H).

Example Number R₁ Accurate Mass (obs.) 15 ethyl 326.1660 161-methylethyl 340.1825 17 butyl 354.1982 18 phenyl 374.1663 19 2-thienyl380.1234 20 benzyl 388.1835 21 3-fluorophenyl 392.1568 22 3-cyanophenyl399.1627 23 4-methoxyphenyl 404.1777 24 1-naphthyl 424.1815 258-quinolinyl 425.1779 26 4-trifluoromethylphenyl 442.1528 27 4-biphenyl450.1982 28 4-methylsulfonylphenyl 452.1409 29 4-trifluoromethoxyphenyl458.1455

EXAMPLE 30N-[4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-{(E)-[4-(dimethylamino)phenyl]diazenyl}benzenesulfonamide

Using the method of Examples 15-29 4-dimethylaminoazobenzene-4′-sulfonylchloride was reacted with of1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine toprovide the desired product. The observed accurate mass was 521.2452.

EXAMPLE 31N′-[4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N,N-dimethylsulfamide

Using the method of Examples 15-29, dimethylsulfamoyl chloride wasreacted with1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine toprovide the desired product. The observed accurate mass was 341.1770.

EXAMPLES 32-46

The compounds in the table below were prepared using the followingmethod. The appropriate sulfonyl chloride (1.1 eq.) was added to a testtube containing a solution of1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine(25 mg, see Example 10 Part F) in chloroform (5 mL). The test tube wascapped and then placed on a shaker at ambient temperature for 16 hours.The solvent was removed by vacuum centrifugation. The residue waspurified by prep HPLC using the method described above to provide thetrifluoroacetate salt of the desired compound. The table below shows thestructure of the free base and the observed accurate mass (m+H).

Example Number R₁ Accurate Mass (obs.) 32 ethyl 370.1929 331-methylethyl 384.2086 34 butyl 398.2231 35 2-thienyl 424.1493 36 benzyl432.2084 37 3-fluorophenyl 436.1834 38 4-cyanophenyl 443.1887 393-cyanophenyl 443.1879 40 4-methoxyphenyl 448.2025 41 2,4-difluorophenyl454.1734 42 1-naphthyl 468.2094 43 8-quinolinyl 469.2037 444-trifluoromethylphenyl 486.1799 45 4-methylsulfonylphenyl 496.1714 464-trifluoromethoxyphenyl 502.1743

EXAMPLE 47N-[4-(4-amino-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-{(E)-[4-(dimethylamino)phenyl]diazenyl}benzenesulfonamide

Using the method of Examples 32-46,4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amineto provide the desired product. The observed accurate mass was 565.2720.

EXAMPLE 48N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}-1-[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonamide

Using the method of Examples 32-46, D-(+)-10-camphorsulfonyl chloridewas reacted with1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amineto provide the desired product. The observed accurate mass was 565.2720.

EXAMPLES 49-56

The compounds in the table below were prepared using the followingmethod. The appropriate sulfonyl chloride (1.1 eq.) was added to a testtube containing a solution of2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine(25 mg, see Example 11 Part F) in chloroform (5 mL). The test tube wascapped and then placed on a shaker at ambient temperature for 16 hours.The solvent was removed by vacuum centrifugation. The residue waspurified by prep HPLC using the method described above to provide thetrifluoroacetate salt of the desired compound. The table below shows thestructure of the free base and the observed accurate mass (m+H).

Example Number R₁ Accurate Mass (obs.) 49 ethyl 424.2396 501-methylethyl 438.2568 51 butyl 452.2714 52 2-naphthyl 522.2540 538-quinolinyl 523.2477 54 4-trifluoromethylphenyl 540.2270 55 4-biphenyl548.2716 56 4-methylsulfonylphenyl 550.2144

EXAMPLE 571-(2-{1-[4-(4-dimethylaminophenylazo)benzenesulfonyl]piperidin-4-yl}ethyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine

Using the method of Examples 49-56,4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amineto provide the desired product. The observed accurate mass was 619.3185.

EXAMPLE 584-{2-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]ethyl}-N,N-dimethylpiperidine-1-sulfonamide

Using the method of Examples 49-56, dimethylsulfamoyl chloride wasreacted with2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amineto provide the desired product. The observed accurate mass was 439.2510.

EXAMPLE 591-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine

Part A

Using the general method of Example 15 Part E, tert-butyl4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate(3.41 g, 8.51 mmol) was reacted with trimethyl orthobutyrate (1.50 mL,9.37 mmol) to provide 3.2 g of crude tert-butyl4-(6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamateas purplish semisolid.

Part B

A mixture of the material from Part A and ammonium acetate (32 g) washeated in a sealed tube at 150° C. overnight. More ammonium acetate (10g) was added, the pressure flask was resealed and the mixture was heatedat 160° C. for 20 hours. The reaction mixture was allowed to cool toambient temperature then it was diluted with water, made basic withammonium hydroxide, saturated with solid sodium chloride and thenextracted with chloroform (×4). The extracts were combined, washed withbrine, dried over magnesium sulfate and then concentrated under reducedpressure to provide a yellow solid. This solid was dissolved inchloroform, washed with 2% sodium hydroxide, dried over magnesiumsulfate and then concentrated under reduced pressure to provide a yelloworange solid. This solid was recrystallized from isopropanol to provideN-[4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]acetamideas a solid, m.p. 200.1-201.4° C.

Analysis: Calculated for C₁₇H₂₇N₅O: % C, 64.32; % H, 8.57; % N, 22.06;Found: % C, 64.21; % H, 8.49; % N, 21.96.

Part C

N-[4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]acetamidewas combined with 6 N hydrochloric acid (75 mL) in a pressure vessel.The vessel was sealed and then heated at 100° C. overnight. Anadditional 1 mL of 6 N hydrochloric acid was added and heating wascontinued for 6 more hours. The reaction mixture was allowed to cool toambient temperature overnight and then it was extracted with ethylacetate (×2). The aqueous layer was cooled in an ice bath, made basic(pH 13) with 50% sodium hydroxide, saturated with sodium chloride, andthen extracted with chloroform (×3). The combined organics were washedwith brine, dried over magnesium sulfate and then concentrated underreduced pressure to provide 0.98 g of1-(4-aminobutyl)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amineas a tan solid.

Part D

Chloropropanesulfonyl chloride (0.221 mL, 1.82 mmol) was added drop wiseto a chilled (0° C.) solution of1-(4-aminobutyl)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine(0.500 g, 1.82 mmol) in dichloromethane (10 mL). The reaction mixturewas allowed to stir for 20 minutes after the addition was completed thentriethylamine (0.245 mL, 2.51 mmol) was added drop wise. The reactionmixture was allowed to stir for 20 minutes after the addition wascompleted then it was poured into water. The layers were separated. Theorganic layer was washed with brine, dried over magnesium sulfate andthen concentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (10 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.272mL, 1.82 mmol) was added and the reaction mixture was allowed to stirovernight. The reaction mixture was poured into water and then extractedwith chloroform (×3). The combined extracts were washed with water thenwith brine, dried over magnesium sulfate and then concentrated underreduced pressure to provide a yellowish oil. The oil was dissolved inacetonitrile and then concentrated under reduced pressure to provide ayellowish white solid. This material was recrystallized from isopropanolto provide 0.53 g of1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amineas a yellow orange solid, m.p. 155.1-161.2° C.

Analysis: Calculated for C₁₈H₂₉N₅O₂S: % C, 56.97; % H, 7.70; % N, 18.45;Found: % C, 56.61; % H, 7.77; % N, 18.14. ¹H NMR (300 MHz, DMSO-d₆) δ5.67 (s, 2 H), 4.21 (apparent t, J=7.5 Hz, 2 H), 3.2-3.08 (m, 4 H), 2.92(t, J=6.5 Hz, 2 H), 2.77 (t, J=7.5 Hz, 2 H), 2.37 (s, 3 H), 2.30 (s, 3H), 2.19 (quintet, J=6.7 Hz, 2 H), 1.78 (sextet, J=7.4 Hz, 2 H),1.73-1.55 (m, 4 H), 1.00 (t, J=7.4 Hz, 3 H); MS (CI) m/e 380.2117(380.2120 calcd for C₁₈H₂₉N₅O₂S, M+H).

EXAMPLES 60-69

The compounds in the table below were prepared using the followingmethod. The appropriate sulfonyl chloride (1.1 eq.) was added to a testtube containing a solution of1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (25mg; see Example 12, Part F) in chloroform (5 mL). The test tube wascapped, vortexed and then placed on a shaker at ambient temperature for16 hours. The solvent was removed by vacuum centrifugation. The residuewas purified by prep HPLC using the method described above to providethe trifluoroacetate salt of the desired compound. The table below showsthe structure of the free base and the observed accurate mass (m+H).

Example Number R₁ Accurate Mass (obs.) 60 ethyl 326.1654 611-methylethyl 340.1821 62 butyl 354.1973 63 2-thienyl 380.1224 643-fluorophenyl 392.1559 65 3-cyanophenyl 399.1606 66 1-naphthyl 424.181967 2-naphthyl 424.1811 68 4-biphenyl 450.1970 694-trifluoromethoxyphenyl 458.1479

EXAMPLE 70N′-[4-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]-N,N-dimethylsulfamide

Using the method of Examples 60-69, dimethylsulfamoyl chloride wasreacted with1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine toprovide the desired product. The observed accurate mass was 341.1770.

EXAMPLE 71

Using the method of Examples 60-69, D-(+)-10-camphorsulfonyl chloridewas reacted with1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine toprovide the desired product. The observed accurate mass was 448.2317.

EXAMPLES 72-87

The compounds in the table below were prepared using the followingmethod. The appropriate sulfonyl chloride (1.1 eq.) was added to a testtube containing a solution of1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine(25 mg; see Example 13 Part C) in chloroform (5 mL). The test tube wascapped, vortexed and then placed on a shaker at ambient temperature for˜17 hours. The solvent was removed by vacuum centrifugation. The residuewas purified by prep HPLC using the method described above to providethe trifluoroacetate salt of the desired compound. The table below showsthe structure of the free base and the observed accurate mass (m+H).

Example Number R₁ Accurate Mass (obs.) 72 ethyl 370.1920 731-methylethyl 384.2046 74 butyl 398.2224 75 phenyl 418.1924 76 2-thienyl424.1476 77 beta-styrenyl 444.2072 78 3-fluorophenyl 436.1823 794-cyanophenyl 443.1876 80 3-cyanophenyl 443.1806 81 4-methoxyphenyl448.1994 82 2,4-difluorophenyl 454.1719 83 1-naphthyl 468.2045 842-naphthyl 468.2056 85 4-trifluoromethylphenyl 486.1780 86 4-biphenyl494.2245 87 4-methylsulfonylphenyl 496.1699

EXAMPLE 88N′-[4-(4-amino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]-N,N-dimethylsulfamide

Using the method of Examples 72-87, dimethylsulfamoyl chloride wasreacted with1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amineto provide the desired product. The observed accurate mass was 385.2001.

EXAMPLE 89

Using the method of Examples 72-87, D-(+)-10-camphorsulfonyl chloridewas reacted with1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amineto provide the desired product. The observed accurate mass was 492.2629.

EXAMPLES 90-112

Part A

A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (60 g, 271 mmol)in anhydrous N,N-dimethylformamide (600 mL) was cooled to 0° C.Triethylamine (44.8 mL, 326 mmol) was added drop wise followed bytert-butyl 2-aminoethylcarbamate (52.2 g, 326 mmol). After 30 minutesthe ice bath was removed and the reaction mixture was heated to 60° C.The reaction was heated at 60° C. overnight and then it was concentratedunder reduced pressure to provide an orange oil. The oil was dissolvedin ethyl acetate (1 L), washed with water (3×500 mL), dried overmagnesium sulfate and then concentrated under reduced pressure toprovide a yellow oil. The oil was triturated with methanol (˜100 mL).The resulting solid was isolated by filtration and washed with coldmethanol to provide 72.3 g of tert-butyl2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethylcarbamate as asolid.

Part B

Phenol (1.19 g, 12.6 mmol) was added in portions to a chilled (0° C.)suspension of sodium hydride (0.52 g of 60%, 13.1 mmol) in diglyme (4mL). The reaction mixture was then stirred for 30 minutes. A warmsolution of tert-butyl2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethylcarbamate (3.0g, 8.70 mmol) in diglyme (6 mL) was added and the reaction mixture washeated at 90° C. overnight. The reaction mixture was cooled and pouredslowly into water (100 mL). The resulting tan solid was isolated byfiltration, washed with water, dried and then recrystallized fromisopropanol (25 mL) to provide 2.07 g of tert-butyl2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethylcarbamate aswhite needles. The reaction was repeated using 66.5 g of startingmaterial to provide 50.4 g of product as white needles, m.p. 158-160° C.

Part C

Catalyst (5 g of 5% platinum on carbon) was added to a warm solution oftert-butyl2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethylcarbamate(50.4 g) in a mixture of toluene (500 mL) and methanol (40 mL). Themixture was placed under hydrogen pressure (50 psi, 3.4×10⁵ Pa). After 2hours more catalyst (4 g) was added and the hydrogenation continuedovernight. The reaction mixture was filtered through a layer of Celite®filter aid and the filter cake was washed with hot toluene (1 L). Thefiltrate was concentrated under reduced pressure to provide 45.1 g oftert-butyl2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethylcarbamate as awhite solid.

Part D

A mixture of tert-butyl2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethylcarbamate(43.7 g, 117 mmol), triethyl orthoacetate (22.6 mL, 123 mmol), pyridinehydrochloride (4.4 g) and toluene (440 mL) was heated at reflux for 30minutes. The reaction mixture was concentrated under reduced pressure toprovide a brown oil. The oil was dissolved in ethyl acetate (1 L) andwashed with water (2×500 mL). The aqueous washes were combined andextracted with ethyl acetate (2×500 mL). The combined organics werewashed with brine, dried over magnesium sulfate and then concentratedunder reduced pressure to provide 46.4 g of tert-butyl2-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)ethylcarbamateas a white solid, m.p. 180-182° C.

Part E

A mixture of ammonium acetate (95 g) and tert-butyl2-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)ethylcarbamate(9.5 g) was heated at 160° C. in a sealed tube for 24 hours. Thereaction mixture was allowed to cool to ambient temperature and then itwas partitioned between water and chloroform. The aqueous layer was madebasic (pH 13) with 50% sodium hydroxide and then extracted withchloroform (10×400 mL). The combined organics were dried over magnesiumsulfate and then concentrated under reduced pressure to provide a brownsolid. The solid was dissolved in warm isopropanol (80 mL) and thencombined with 1M hydrochloric acid in diethyl ether (23.7 mL). Theresulting precipitate was isolated by filtration, washed with coldisopropanol and diethyl ether, and then dried in a vacuum oven at 80° C.overnight to provide 5.0 g ofN-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethyl]acetamidehydrochloride as a white solid, m.p.>250° C. Analysis: Calculated for:C₁₃H₁₉N₅O.1.00 HCl: % C, 52.43; % H, 6.77; % N, 23.52; Found: % C,52.25; % H, 6.81; % N, 23.41.

The reaction was repeated using 34 g of starting material to provide 18g of the acetamide hydrochloride as a light tan solid.

Part F

N-[2-(4-Amino-2,6,7-trimethyl-1H-imidao[4,5-c]pyridin-1-yl)ethyl]acetamidehydrochloride (18 g), hydrochloric acid (231 mL) and ethanol (350 mL)were combined and heated at 90° C. overnight. The reaction mixture wasallowed to cool to ambient temperature and then it was diluted withdiethyl ether (200 mL). The resulting precipitate was isolated byfiltration, washed with cold ethanol and with diethyl ether, and thendried under vacuum at 80° C. overnight to provide 17.3 g of1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-aminehydrochloride as white needles.

Analysis: Calculated for C₁₁H₁₇N₅.2.8 HCl.0.25 H₂O: % C, 40.32; % H,6.26; % N, 30.83; Found: % C, 40.54; % H, 6.15; % N, 30.87. ¹H NMR (300MHz, DMSO-d₆) δ 8.19 (t, J=6.2 Hz, 1 H), 7.91 (s, 2 H), 4.34 (t, J=6.6Hz, 2 H), 3.39 (quartet, J=6.4 Hz, 2 H), 2.56 (s, 3 H), 2.43 (d, J=8.1Hz, 6 H), 1.77 (s, 3 H); MS(CI) m/e 262 (M+H)

A 3 g portion of the material was dissolved in water (150 mL) and thencombined with sodium carbonate (30 g). The mixture was stirred for 30minutes and then extracted with chloroform on a continuous extractorovernight. The chloroform extract was dried over magnesium sulfate andthen concentrated under reduced pressure to provide 1.7 g of the freebase as a light tan solid.

Part G

The compounds in the table below were prepared using the followingmethod. The appropriate sulfonyl chloride (1.1 eq.) was added to a testtube containing a solution of1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (20mg) in chloroform (5 mL). The test tube was capped, vortexed and thenplaced on a shaker at ambient temperature for 4 hours. The solvent wasremoved by vacuum centrifugation. The residue was purified by prep HPLCusing the method described above to provide the trifluoroacetate salt ofthe desired compound. The table below shows the structure of the freebase and the observed accurate mass (m+H).

Example Number R₁ Accurate Mass (obs.) 90 ethyl 312.1483 911-methylethyl 326.1630 92 butyl 340.1812 93 phenyl 360.1474 94 2-thienyl366.1052 95 beta-styrenyl 386.1646 96 3-fluorophenyl 378.1406 974-cyanophenyl 385.1449 98 3-cyanophenyl 385.1432 99 4-methoxyphenyl390.1586 100 2,4-difluorophenyl 396.1318 101 1-naphthyl 410.1641 1022-naphthyl 410.1650 103 4-trifluoromethylphenyl 428.1358 104 4-biphenyl436.1791 105 4-methylsulfonylphenyl 438.1272 1064-trifluoromethoxyphenyl 444.1315 107 1-methylimidazol-4-yl 364.1563 1083,5-dimethylisoxazol-4-yl 379.1545 109 5-chlorothien-2-yl 400.0665 1104-benzoic acid 404.1388 111 2-nitrobenzyl 419.1501 1122-(benzoylaminomethyl)thien-5-yl 499.1567

EXAMPLE 113N′-[4-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethyl]-N,N-dimethylsulfamide

Using the method of Examples 90-112, dimethylsulfamoyl chloride wasreacted with1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine toprovide the desired product. The observed accurate mass was 327.1621.

EXAMPLE 114

Using the method of Examples 90-112, D-(+)-10-camphorsulfonyl chloridewas reacted with1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine toprovide the desired product. The observed accurate mass was 434.2217.

EXAMPLES 115-135

The compounds in the table below were prepared using the followingmethod. The appropriate sulfonyl chloride (1.1 eq.) was added to a testtube containing a solution of1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4amine(23.5 mg; see Example 14, Part H) in chloroform (5 mL). The test tubewas capped and then placed on a shaker at ambient temperature for 4hours. The solvent was removed by vacuum centrifugation. The residue waspurified by prep HPLC using the method described above to provide thetrifluoroacetate salt of the desired compound. The table below shows thestructure of the free base and the observed accurate mass (m+H).

Example Number R₁ Accurate Mass (obs.) 115 ethyl 370.1925 1161-methylethyl 384.2076 117 butyl 398.220 118 phenyl 418.1920 1192-thienyl 424.1450 120 beta-styrenyl 444.2059 121 3-fluorophenyl436.1787 122 4-cyanophenyl 443.1865 123 3-cyanophenyl 443.1881 1244-methoxyphenyl 448.1998 125 2,4-difluorophenyl 454.1713 126 1-naphthyl468.2056 127 2-naphthyl 468.2045 128 4-trifluoromethylphenyl 486.1795129 4-biphenyl 494.2221 130 4-methylsulfonylphenyl 496.1684 1314-trifluoromethoxyphenyl 502.1747 132 1-methylimidazol-4-yl 422.1985 1333,5-dimethylisoxazol-4-yl 437.1982 134 5-chlorothien-2-yl 458.1097 1352-(benzoylaminomethyl)thien-5-yl 557.2028

EXAMPLE 136N′-[4-(4-amino-2-ethoxymethyl-7-methyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N,N-dimethylsulfamide

Using the method of Examples 115-135, dimethylsulfamoyl chloride wasreacted with1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amineto provide the desired product. The observed accurate mass was 385.2029.

EXAMPLE 137

Using the method of Examples 115-135, D-(+)-10-camphorsulfonyl chloridewas reacted with1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amineto provide the desired product. The observed accurate mass was 492.2655.

CYTOKINE INDUCTION IN HUMAN CELLS

An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon and tumornecrosis factor (α) (IFN and TNF, respectively) secreted into culturemedia as described by Testerman et. al. In “Cytokine Induction by theImmunomodulators Imiquimod and S-27609”, Journal of Leukocyte Biology,58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intoEDTA vacutainer tubes. Peripheral blood mononuclear cells (PBMC) areseparated from whole blood by density gradient centrifugation usingHistopaque®-1077. Blood is diluted 1:1 with Dulbecco's PhosphateBuffered Saline (DPBS) or Hank's Balanced Salts Solution (HBSS). ThePBMC layer is collected and washed twice with DPBS or HBSS andresuspended at 4×10⁶ cells/mL in RPMI complete. The PBMC suspension isadded to 48 well flat bottom sterile tissue culture plates (Costar,Cambridge, Mass. or Becton Dickinson Labware, Lincoln Park, N.J.)containing an equal volume of RPMI complete media containing testcompound.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM.

Incubation

The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(30-0.014 μM). The final concentration of PBMC suspension is 2×10⁶cells/mL. The plates are covered with sterile plastic lids, mixed gentlyand then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxideatmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (˜200×g) at 4° C. The cell-free culture supernatant is removed witha sterile polypropylene pipet and transferred to sterile polypropylenetubes. Samples are maintained at −30 to −70° C. until analysis. Thesamples are analyzed for interferon (α) by ELISA and for tumor necrosisfactor (α) by ELISA or IGEN Assay

Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA

Interferon (α) concentration is determined by ELISA using a HumanMulti-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J.Results are expressed in pg/mL.

Tumor necrosis factor (α) (TNF) concentration is determined using ELISAkits available from Biosource International, Camarillo, Calif.Alternately, the TNF concentration can be determined by Origen® M-SeriesImmunoassay and read on an IGEN M-8 analyzer from IGEN International,Gaithersburg, Md. The immunoassay uses a human TNF capture and detectionantibody pair from Biosource International, Camarillo, Calif. Resultsare expressed in pg/mL.

The table below lists the lowest concentration found to induceinterferon and the lowest concentration found to induce tumor necrosisfactor for each compound. A “*” indicates that no induction was seen atany of the tested concentrations.

Cytokine Induction in Human Cells Example Lowest Effective Concentration(μM) Number Interferon Tumor Necrosis Factor 1 0.12 1.11 2 0.0046 0.01 30.01 0.37 4 0.12 0.37 5 0.01 0.12 6 0.01 0.01 7 0.37 * 8 0.04 10 11 0.373.33 15 10 * 16 10 10 17 30 * 18 30 * 19 10 * 20 * * 21 * 30 22 * * 231.11 * 24 * * 25 * * 26 * * 27 * 30 28 * * 29 * * 30 * * 31 10 10 321.11 10 33 1.11 10 34 3.33 10 35 1.11 3.33 36 3.33 10 37 3.33 3.33 383.33 3.33 39 10 10 40 3.33 3.33 41 1.11 1.11 42 3.33 10 43 3.33 3.33 443.33 * 45 3.33 * 46 3.33 * 47 * * 48 3.33 30 49 3.33 3.33 50 1.11 3.3351 1.11 10 52 * * 53 0.12 1.11 54 * * 55 * * 56 0.37 1.11 57 * * 58 1.113.33

The present invention has been described with reference to severalembodiments thereof. The foregoing detailed description and exampleshave been provided for clarity of understanding only, and no unnecessarylimitations are to be understood therefrom. It will be apparent to thoseskilled in the art that many changes can be made to the describedembodiments without departing from the spirit and scope of theinvention. Thus, the scope of the invention should not be limited to theexact details of the compositions and structures described herein, butrather by the language of the claims that follow.

1. A compound of the formula (I):

wherein X is alkylene of 1 to 10 carbon atoms; Y is —SO₂—; Z is a bond;R₁ is C₁₋₄ alkyl; R₂ is selected from the group consisting of:—C₁₋₁₀alkyl; and —C₁₋₁₀alkyl-O—C₁₋₁₀alkyl; R₃ and R₄ are methyl; and R₅is hydrogen; or a pharmaceutically acceptable salt thereof.
 2. Thecompound or salt of claim 1 wherein R₂ is alkyl of 1 to 4 carbon atoms,methoxyethyl, or ethoxymethyl.
 3. The compound or salt of claim 1wherein R₁ is methyl, and R₂ is butyl or ethoxymethyl.
 4. The compoundor salt of claim 1 wherein R₁ is methyl; R₂ is butyl or ethoxymethyl;and X is butylene.
 5. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 in combinationwith a pharmaceutically acceptable carrier.
 6. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 2 in combination with a pharmaceutically acceptable carrier. 7.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 3 in combination with a pharmaceuticallyacceptable carrier.
 8. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 4 in combinationwith a pharmaceutically acceptable carrier.
 9. A method of inducingcytokine biosynthesis in an animal comprising administering an effectiveamount of a compound of claim 1 to the animal.
 10. A method of treatinga viral disease in an animal comprising administering a therapeuticallyeffective amount of a compound of claim 1 to the animal.
 11. A method oftreating a neoplastic disease in an animal comprising administering atherapeutically effective amount of a compound of claim 1 to the animal.12. A method of inducing cytokine biosynthesis in an animal comprisingadministering an effective amount of a compound of claim 2 to theanimal.
 13. A method of treating a viral disease in an animal comprisingadministering a therapeutically effective amount of a compound of claim2 to the animal.
 14. A method of treating a neoplastic disease in ananimal comprising administering a therapeutically effective amount of acompound of claim 2 to the animal.
 15. A method of inducing cytokinebiosynthesis in an animal comprising administering an effective amountof a compound of claim 3 to the animal.
 16. A method of treating a viraldisease in an animal comprising administering a therapeuticallyeffective amount of a compound of claim 3 to the animal.
 17. A method oftreating a neoplastic disease in an animal comprising administering atherapeutically effective amount of a compound of claim 3 to the animal.18. A method of inducing cytokine biosynthesis in an animal comprisingadministering an effective amount of a compound of claim 4 to theanimal.
 19. A method of treating a viral disease in an animal comprisingadministering a therapeutically effective amount of a compound of claim4 to the animal.
 20. A method of treating a neoplastic disease in ananimal comprising administering a therapeutically effective amount of acompound of claim 4 to the animal.